Human Tissue-Resident Mucosal-Associated Invariant T (MAIT) Cells in Renal Fibrosis and CKD.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells represent a specialized lymphocyte population associated with chronic inflammatory disorders. Little is known, however, about MAIT cells in diseases of the kidney, including CKD. METHODS: To evaluate MAIT cells in human native kidneys with tubulointerstitial fibrosis, the hallmark of CKD, we used multicolor flow cytometry to identify, enumerate, and phenotype such cells from human kidney tissue biopsy samples, and immunofluorescence microscopy to localize these cells. We cocultured MAIT cells and human primary proximal tubular epithelial cells (PTECs) under hypoxic (1% oxygen) conditions to enable examination of mechanistic tubulointerstitial interactions. RESULTS: We identified MAIT cells (CD3+ TCR Vα7.2+ CD161hi) in healthy and diseased kidney tissues, detecting expression of tissue-resident markers (CD103/CD69) on MAIT cells in both states. Tissue samples from kidneys with tubulointerstitial fibrosis had significantly elevated numbers of MAIT cells compared with either nonfibrotic samples from diseased kidneys or tissue samples from healthy kidneys. Furthermore, CD69 expression levels, also an established marker of lymphocyte activation, were significantly increased on MAIT cells from fibrotic tissue samples. Immunofluorescent analyses of fibrotic kidney tissue identified MAIT cells accumulating adjacent to PTECs. Notably, MAIT cells activated in the presence of human PTECs under hypoxic conditions (modeling the fibrotic microenvironment) displayed significantly upregulated expression of CD69 and cytotoxic molecules perforin and granzyme B; we also observed a corresponding significant increase in PTEC necrosis in these cocultures. CONCLUSIONS: Our findings indicate that human tissue-resident MAIT cells in the kidney may contribute to the fibrotic process of CKD via complex interactions with PTECs.

Variation and Interactional Non-Standardization in Neuropsychological Tests: The Case of the Addenbrooke's Cognitive Examination.

The Addenbrooke's Cognitive Examination (ACE-111) is a neuropsychological test used in clinical practice to inform a dementia diagnosis. The ACE-111 relies on standardized administration so that patients' scores can be interpreted by comparison with normative scores. The test is delivered and responded to in interaction between clinicians and patients, which places talk-in-interaction at the heart of its administration. In this article, conversation analysis (CA) is used to investigate how the ACE-111 is delivered in clinical practice. Based on analysis of 40 video/audio-recorded memory clinic consultations in which the ACE-111 was used, we have found that administrative standardization is rarely achieved in practice. There was evidence of both (a) interactional variation in the way the clinicians introduce the test and (b) interactional non-standardization during its implementation. We show that variation and interactional non-standardization have implications for patients' understanding and how they might respond to particular questions.

Effector γδ T cells in human renal fibrosis and chronic kidney disease.

Background: γδ T cells are effector lymphocytes recognized as key players during chronic inflammatory processes. Mouse studies suggest a pathological role for γδ T cells in models of kidney disease. Here we evaluated γδ T cells in human native kidneys with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Methods: γδ T cells were extracted from human kidney tissue and enumerated and phenotyped by multicolour flow cytometry. Localization and cytokine production by γδ T cells was examined by immunofluorescent microscopy. Results: We detected significantly elevated numbers of γδ T cells in diseased biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue. At a subset level, only numbers of Vδ1+ γδ T cells were significantly elevated in fibrotic kidney tissue. Expression levels of cluster of differentiation 161 (CD161), a marker of human memory T cells with potential for innate-like function and interleukin (IL)-17A production, were significantly elevated on γδ T cells from fibrotic biopsies compared with nonfibrotic kidney tissue. Flow cytometric characterization of CD161+ γδ T cells in fibrotic biopsies revealed significantly elevated expression of natural killer (NK) cell-associated markers CD56, CD16 and CD336 (NKp44) compared with CD161- γδ T cells, indicative of a cytotoxic phenotype. Immunofluorescent analysis of fibrotic kidney tissue localized the accumulation of γδ T cells within the tubulointerstitium, with γδ T cells identified, for the first time, as a source of pro-inflammatory cytokine IL-17A. Conclusions: Collectively, our data suggest that human effector γδ T cells contribute to the fibrotic process and thus progression to chronic kidney disease.

Taking turns: bridging the gap between human and animal communication.

Language, humans' most distinctive trait, still remains a 'mystery' for evolutionary theory. It is underpinned by a universal infrastructure-cooperative turn-taking-which has been suggested as an ancient mechanism bridging the existing gap between the articulate human species and their inarticulate primate cousins. However, we know remarkably little about turn-taking systems of non-human animals, and methodological confounds have often prevented meaningful cross-species comparisons. Thus, the extent to which cooperative turn-taking is uniquely human or represents a homologous and/or analogous trait is currently unknown. The present paper draws attention to this promising research avenue by providing an overview of the state of the art of turn-taking in four animal taxa-birds, mammals, insects and anurans. It concludes with a new comparative framework to spur more research into this research domain and to test which elements of the human turn-taking system are shared across species and taxa.

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression.

Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3-CD56+) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56dim NK cell subset and particularly the CD56bright NK cell subset were elevated in fibrotic kidney tissue. However, only CD56bright NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56bright NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56bright NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56bright NK cells (NKp46+ CD117+) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56bright NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease.

Everyday conversation in dementia: a review of the literature to inform research and practice.

BACKGROUND: There has been increasing interest in dementia care in recent years, including how practitioners, service providers and society in general can help individuals to live well with the condition. An important aspect to this is provision of advice to ensure conversation partners effectively support the person with dementia in conversation. AIMS: To provide a descriptive review of the literature examining everyday conversation in dementia in order to inform practice and research. METHODS & PROCEDURES: This review used a method specifically developed for reviewing conversation analytic and related literature. A range of databases were searched using key words and explicitly described inclusion criteria leading to a final corpus of 50 titles. Using this qualitative methodology, each paper was examined and data extracted. The contribution of each of these is described and the implications for practice and research are outlined. MAIN CONTRIBUTION: This review examined studies into conversation in Alzheimer's disease, vascular dementia and Lewy body dementia, grouping these into: early influential studies; work drawing on positioning theory; studies using social and linguistic approaches; collaborative storytelling; formulaic language; studies specifically using conversation analysis; and conversation as a target for individualized therapy. In addition, more recent work examining primary progressive aphasia and behavioural variant frontotemporal dementia was explored. Overall, this review indicates that research examining conversation in natural settings provides a rich source of data to explore not just the challenges within conversation for those taking part, but also the skills retained by the person with dementia. An important aspect of this understanding is the notion that these skills relate not only to information exchange but also aspects of social interaction. The role of others in scaffolding the conversation abilities of the person with dementia and the potential of this for developing interventions are discussed. CONCLUSIONS & IMPLICATIONS: The review indicates that interventions targeting conversation in dementia are often advocated in the literature but currently such approaches remain to be systematically evaluated. In addition, many of the important insights arising from these studies have yet to inform multidisciplinary dementia care practice.

Fractalkine-CX3CR1-dependent recruitment and retention of human CD1c+ myeloid dendritic cells by in vitro-activated proximal tubular epithelial cells.

Chemokines play pivotal roles in tissue recruitment and retention of leukocytes, with CX3CR1 recently identified as a chemokine receptor that selectively targets mouse kidney dendritic cells (DCs). We have previously demonstrated increased tubulointerstitial recruitment of human transforming growth factor-ß (TGF-ß)-producing DCs in renal fibrosis and chronic kidney disease (CKD). However, little is known about the mechanism of human DC recruitment and retention within the renal interstitium. We identified CD1c+ DCs as the predominant source of profibrotic TGF-ß and highest expressors of the fractalkine receptor CX3CR1 within the renal DC compartment. Immunohistochemical analysis of diseased human kidney biopsies showed colocalization of CD1c+ DCs with fractalkine-positive proximal tubular epithelial cells (PTECs). Human primary PTEC activation with interferon-γ and tumor necrosis factor-α induced both secreted and surface fractalkine expression. In line with this, we found fractalkine-dependent chemotaxis of CD1c+ DCs to supernatant from activated PTECs. Finally, in comparison with unactivated PTECs, we showed significantly increased adhesion of CD1c+ DCs to activated PTECs via a fractalkine-dependent mechanism. Thus, TGF-ß-producing CD1c+ DCs are recruited and retained in the renal tubulointerstitium by PTEC-derived fractalkine. These cells are then positioned to play a role in the development of fibrosis and progression of chronic kidney disease.

Human proximal tubule epithelial cells modulate autologous B-cell function.

BACKGROUND: Descriptions of inflammatory cells infiltrating the human kidney rarely mention B cells, other than in the specific scenario of transplantation. In these reports, B cells are localized almost exclusively within the kidney tubulointerstitium where they are ideally placed to interact with proximal tubule epithelial cells (PTEC). We have previously shown that activated PTEC down-modulate autologous T lymphocyte and dendritic cell function. In this report, we extend these prior studies to describe PTEC-B cell interactions. METHODS: Stimulated B cells were cultured in the absence or presence of activated autologous human PTEC and monitored for proliferation, surface antigen expression, cytokine secretion and antibody (Ab) production. RESULTS: PTEC decreased B cell proliferative responses, whilst B cells cultured in the presence of PTEC displayed decreased levels of CD27, a marker of plasma B cells and memory cells. Interestingly, autologous PTEC also significantly decreased the number of B cells secreting both IgG and IgM and overall levels of Ab production. Transwell studies demonstrated that this modulation was primarily contact-dependent, and blocking studies with anti-PD-L1 led to partial restoration in Ab production. Further blocking studies targeting soluble HLA-G (sHLA-G) and IDO, two other immunoinhibitory molecules also up-regulated in our activated PTEC, demonstrated minor restoration of Ab responses. DISCUSSION: We report, for the first time, that PTEC are also able to modulate autologous B-cell phenotype and function via complex contact-dependent (PD-L1), soluble (sHLA-G) and intracellular (IDO) factors. We hypothesize that such mechanisms may have evolved to maintain peripheral immune-homeostasis, especially within the inflammatory milieu that exists within many kidney diseases.

Multiple repair sequences in everyday conversations involving people with Parkinson's disease.

BACKGROUND: Features of dysarthria associated with Parkinson's disease (PD), such as low volume, variable rate of speech and increased pauses, impact speaker intelligibility. Those affected report restricted interactional participation, although this area is under explored. AIMS: To examine naturally occurring instances of problems with intelligibility that resulted in multiple attempts at repair in order to consider repair initiation strategies that might restrict or enhance participation. METHODS & PROCEDURES: Thirteen people with PD (PwPD) video-recorded over 10 h of informal conversation data in their home setting involving familiar conversation partners (CPs). Using a conversation analytic (CA) approach, and drawing on an existing typology of repair initiators (RIs) for everyday talk-in-interaction and their relative power to locate a turn's repairable element, the design and ordering of RIs used by CPs was addressed, alongside their local consequences. OUTCOMES & RESULTS: CPs tended to increase the specificity of their RIs in line with the existing typology, progressing from open class forms (e.g. 'mm?') to more specific forms (e.g. questions/partial repeats). Repeated open class repair initiators (OCRIs) were used where PD speakers' self-repair attempts provided limited information. Sometimes, however, specificity was increased too soon, before enough syntactic knowledge was gleaned, which resulted in an extended repair sequence. Where one OCRI followed another, the second always took a different form: lexically or in terms of prosodic/non-verbal features. RI forms not described in the existing typology were also identified, such as 'prompts to modify speech' (e.g. 'Speak louder') and repeating/rephrasing the original first pair part (e.g. question), and their effectiveness examined. CONCLUSIONS & IMPLICATIONS: First steps are presented towards the design of a communication intervention promoting the efficient resolution of repair to moderate social withdrawal and increase participation for this client group. Future research will need to explore the feasibility and acceptability of such a resource.

Living with semantic dementia: a case study of one family's experience.

Semantic dementia is a variant of frontotemporal dementia and is a recently recognized diagnostic condition. There has been some research quantitatively examining care partner stress and burden in frontotemporal dementia. There are, however, few studies exploring the subjective experiences of family members caring for those with frontotemporal dementia. Increased knowledge of such experiences would allow service providers to tailor intervention, support, and information better. We used a case study design, with thematic narrative analysis applied to interview data, to describe the experiences of a wife and son caring for a husband/father with semantic dementia. Using this approach, we identified four themes: (a) living with routines, (b) policing and protecting, (c) making connections, and (d) being adaptive and flexible. Each of these themes were shared and extended, with the importance of routines in everyday life highlighted. The implications for policy, practice, and research are discussed.

Human proximal tubular epithelial cell-derived small extracellular vesicles mediate synchronized tubular ferroptosis in hypoxic kidney injury.

Hypoxia is the key pathobiological trigger of tubular oxidative stress and cell death that drives the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). The mitochondrial-rich proximal tubular epithelial cells (PTEC) are uniquely sensitive to hypoxia and thus, are pivotal in propagating the sustained tubular loss of AKI-to-CKD transition. Here, we examined the role of PTEC-derived small extracellular vesicles (sEV) in propagating the 'wave of tubular death'. Ex vivo patient-derived PTEC were cultured under normoxia (21 % O2) and hypoxia (1 % O2) on Transwell inserts for isolation and analysis of sEV secreted from apical versus basolateral PTEC surfaces. Increased numbers of sEV were secreted from the apical surface of hypoxic PTEC compared with normoxic PTEC. No differences in basolateral sEV numbers were observed between culture conditions. Biological pathway analysis of hypoxic-apical sEV cargo identified distinct miRNAs linked with cellular injury pathways. In functional assays, hypoxic-apical sEV selectively induced ferroptotic cell death (↓glutathione peroxidase-4, ↑lipid peroxidation) in autologous PTEC compared with normoxic-apical sEV. The addition of ferroptosis inhibitors, ferrostatin-1 and baicalein, attenuated PTEC ferroptosis. RNAse A pretreatment of hypoxic-apical sEV also abrogated PTEC ferroptosis, demonstrating a role for sEV RNA in ferroptotic 'wave of death' signalling. In line with these in vitro findings, in situ immunolabelling of diagnostic kidney biopsies from AKI patients with clinical progression to CKD (AKI-to-CKD transition) showed evidence of ferroptosis propagation (increased numbers of ACSL4+ PTEC), while urine-derived sEV (usEV) from these 'AKI-to-CKD transition' patients triggered PTEC ferroptosis (↑lipid peroxidation) in functional studies. Our data establish PTEC-derived apical sEV and their intravesicular RNA as mediators of tubular lipid peroxidation and ferroptosis in hypoxic kidney injury. This concept of how tubular pathology is propagated from the initiating insult into a 'wave of death' provides novel therapeutic check-points for targeting AKI-to-CKD transition.

Increased tubulointerstitial recruitment of human CD141(hi) CLEC9A(+) and CD1c(+) myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease.

Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141(hi) and CD1c(+) myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141(hi) DCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c(+) DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141(hi) and CD1c(+) blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A(+) and CD1c(+) cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-ß levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease.

Human proximal tubule epithelial cells modulate autologous dendritic cell function.

BACKGROUND: We have previously demonstrated that human kidney proximal tubule epithelial cells (PTEC) are able to modulate autologous T and B lymphocyte responses. It is well established that dendritic cells (DC) are responsible for the initiation and direction of adaptive immune responses and that these cells occur in the renal interstitium in close apposition to PTEC under inflammatory disease settings. However, there is no information regarding the interaction of PTEC with DC in an autologous human context. METHODS: Human monocytes were differentiated into monocyte-derived DC (MoDC) in the absence or presence of primary autologous activated PTEC and matured with polyinosinic:polycytidylic acid [poly(I:C)], while purified, pre-formed myeloid blood DC (CD1c(+) BDC) were cultured with autologous activated PTEC in the absence or presence of poly(I:C) stimulation. DC responses were monitored by surface antigen expression, cytokine secretion, antigen uptake capacity and allogeneic T-cell-stimulatory ability. RESULTS: The presence of autologous activated PTEC inhibited the differentiation of monocytes to MoDC. Furthermore, MoDC differentiated in the presence of PTEC displayed an immature surface phenotype, efficient phagocytic capacity and, upon poly(I:C) stimulation, secreted low levels of pro-inflammatory cytokine interleukin (IL)-12p70, high levels of anti-inflammatory cytokine IL-10 and induced weak Th1 responses. Similarly, pre-formed CD1c(+) BDC matured in the presence of PTEC exhibited an immature tolerogenic surface phenotype, strong endocytic and phagocytic ability and stimulated significantly attenuated T-cell proliferative responses. CONCLUSIONS: Our data suggest that activated PTEC regulate human autologous immunity via complex interactions with DC. The ability of PTEC to modulate autologous DC function has important implications for the dampening of pro-inflammatory immune responses within the tubulointerstitium in renal injuries. Further dissection of the mechanisms of PTEC modulation of autologous immune responses may offer targets for therapeutic intervention in renal medicine.

Adapting to conversation with semantic dementia: using enactment as a compensatory strategy in everyday social interaction.

BACKGROUND: Studies to date in semantic dementia have examined communication in clinical or experimental settings. There is a paucity of research describing the everyday interactional skills and difficulties seen in this condition. AIMS: To examine the everyday conversation, at home, of an individual with semantic dementia. METHODS & PROCEDURES: A 71-year-old man with semantic dementia and his wife were given a video camera and asked to record natural conversation in the home situation with no researcher present. Recordings were also made in the home environment, with the individual with semantic dementia in conversation with a member of the research team. Conversation analysis was used to transcribe and analyse the data. Recurring features were noted to identify conversational patterns. OUTCOMES & RESULTS: Analysis demonstrated a repeated practice by the speaker with semantic dementia of acting out a diversity of scenes (enactment). As such, the speaker regularly used direct reported speech along with paralinguistic features (such as pitch and loudness) and non-vocal communication (such as body posture, pointing and facial expression) as an adaptive strategy to communicate with others in conversation. CONCLUSIONS & IMPLICATIONS: This case shows that while severe difficulties may be present on neuropsychological assessment, relatively effective communicative strategies may be evident in conversation. A repeated practice of enactment in conversation allowed this individual to act out, or perform what he wanted to say, allowing him to generate a greater level of meaningful communication than his limited vocabulary alone could achieve through describing the events concerned. Such spontaneously acquired adaptive strategies require further attention in both research and clinical settings in semantic dementia and analysis of interaction in this condition, using conversation analysis, may be helpful.

Gestural depiction in acquired language disorders: on the form and use of iconic gestures in aphasic talk-in-interaction.

This paper uses conversation analysis to investigate the form and use of iconic gestures by a man with severe Broca-type aphasia in interaction with his speech and language therapist. Deconstructing iconic gestures into the different types of methods used to produce them, the paper analyzes how these gestures can depict certain entities, such as actions or types of people, in ways that may be understandable to the recipient. It is also observed that these iconic gestures can constitute gestural contributions, which not only communicate certain semantic meanings, but also accomplish social actions, such as answering or repairing. The implications of this analysis for our understanding of compensatory behavior in aphasia, and of augmentative and alternative communication in social interaction more generally, are discussed.

Speaker transfer in children's peer conversation: completing communication-aid-mediated contributions.

Managing the exchange of speakers from one person to another effectively is a key issue for participants in everyday conversational interaction. Speakers use a range of resources to indicate, in advance, when their turn will come to an end, and listeners attend to such signals in order to know when they might legitimately speak. Using the principles and findings from conversation analysis, this paper examines features of speaker transfer in a conversation between a boy with cerebral palsy who has been provided with a voice-output communication aid (VOCA), and a peer without physical or communication difficulties. Specifically, the analysis focuses on turn exchange, where a VOCA-mediated contribution approach completion, and the child without communication needs is due to speak next.

The interactional organization of aphasia naming testing.

In this article, Conversation Analysis (CA) is used to investigate the nature of aphasia naming tests in terms of their properties as a specialized form of social interaction. The basic test-item sequence which occurs in these tests is shown to be made up of a three-part sequential structure consisting of (1) a testing prompt, (2) a proffered answer by the testee, and (3) an acceptance or declining of that proffered answer by the tester. A declining prompts a further answer to be proffered, and this cycle continues until either an answer is accepted by the tester or until the participants treat the testee as being unable to produce the relevant picture name. It is suggested that the results of the analysis have implications for understanding naming tests as instruments which generate theoretical and clinical findings through particular talk-in-interaction practices.

Bodies at play: the role of intercorporeality and bodily affordances in coordinating social play in chimpanzees in the wild.

The comparative approach is a crucial method to gain a better understanding of the behavior of living human and nonhuman animals to then draw informed inferences about the behavior of extinct ancestors. One focus has been on disentangling the puzzle of language evolution. Traditionally, studies have predominantly focused on intentionally produced signals in communicative interactions. However, in collaborative and highly dynamic interactions such as play, underlying intentionality is difficult to assess and often interactions are negotiated via body movements rather than signals. This "lack" of signals has led to this dynamic context being widely ignored in comparative studies. The aim of this paper is threefold: First, we will show how comparative research into communication can benefit from taking the intentionality-agnostic standpoint used in conversation analysis. Second, we will introduce the concepts of 'intercorporeality' and 'bodily affordance', and show how they can be applied to the analysis of communicative interactions of nonhuman animals. Third, we will use these concepts to investigate how chimpanzees (Pan troglodytes) initiate, end, and maintain 'contact social play'. Our results showed that bodily affordances are able to capture elements of interactions that more traditional approaches failed to describe. Participants made use of bodily affordances to achieve coordinated engagement in contact social play. Additionally, these interactions could display a sequential organization by which one 'move' by a chimpanzee was responded to with an aligning 'move', which allowed for the co-construction of the activity underway. Overall, the present approach innovates on three fronts: First, it allows for the analysis of interactions that are often ignored because they do not fulfil criteria of intentionality, and/or consist of purely body movements. Second, adopting concepts from research on human interaction enables a better comparison of communicative interactions in other animal species without a too narrow focus on intentional signaling only. Third, adopting a stance from interaction research that highlights how practical action can also be communicative, our results show that chimpanzees can communicate through their embodied actions as well as through signaling. With this first step, we hope to inspire new research into dynamic day-to-day interactions involving both "traditional" signals and embodied actions, which, in turn, can provide insights into evolutionary precursors of human language.

Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients.

Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer, but its application is limited by the lack of suitable target antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly overexpressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201+ KLK4 + cell lines and KLK4 mRNA-transfected monocyte-derived dendritic cells. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.