CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection.

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a role during the initial stages after T. cruzi infection, restraining the magnitude of CD8+ T cell responses and parasite control. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation, exhaustion and functional markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell immunity. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, preventing increased parasite replication in T. cruzi infected mice adoptively transferred with Treg cells. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

CD39+ conventional CD4+ T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade.

Conventional CD4+ T (Tconv) lymphocytes play important roles in tumor immunity; however, their contribution to tumor elimination remains poorly understood. Here, we describe a subset of tumor-infiltrating Tconv cells characterized by the expression of CD39. In several mouse cancer models, we observed that CD39+ Tconv cells accumulated in tumors but were absent in lymphoid organs. Compared to tumor CD39- counterparts, CD39+ Tconv cells exhibited a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of inhibitory receptors and transcription factors related to the exhaustion. Additionally, CD39+ Tconv cells showed increased production of IFNγ, granzyme B, perforin and CD107a expression, but reduced production of TNF. Around 55% of OVA-specific Tconv from B16-OVA tumor-bearing mice, expressed CD39. In vivo CTLA-4 blockade induced the expansion of tumor CD39+ Tconv cells, which maintained their cytotoxic and exhausted features. In breast cancer patients, CD39+ Tconv cells were found in tumors and in metastatic lymph nodes but were less frequent in adjacent non-tumoral mammary tissue and not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constituted a heterogeneous cell population with features of exhaustion, high expression of inhibitory receptors and CD107a. We found that high CD4 and ENTPD1 (CD39) gene expression in human tumor tissues correlated with a higher overall survival rate in breast cancer patients. Our results identify CD39 as a biomarker of Tconv cells, with characteristics of both exhaustion and cytotoxic potential, and indicate CD39+ Tconv cells as players within the immune response against tumors.

Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells.

IL-17 immune responses in cancer are controversial, with both tumor-promoting and tumor-repressing effects observed. To clarify the role of IL-17 signaling in cancer progression, we used syngeneic tumor models from different tissue origins. We found that deficiencies in host IL-17RA or IL-17A/F expression had varying effects on the in vivo growth of different solid tumors including melanoma, sarcoma, lymphoma, and leukemia. In each tumor type, the absence of IL-17 led to changes in the expression of mediators associated with inflammation and metastasis in the tumor microenvironment. Furthermore, IL-17 signaling deficiencies in the hosts resulted in decreased anti-tumor CD8+ T cell immunity and caused tumor-specific changes in several lymphoid cell populations. Our findings were associated with distinct patterns of IL-17A/F cytokine and receptor subunit expression in the injected tumor cell lines. These patterns affected tumor cell responsiveness to IL-17 and downstream intracellular signaling, leading to divergent effects on cancer progression. Additionally, we identified IL-17RC as a critical determinant of the IL-17-mediated response in tumor cells and a potential biomarker for IL-17 signaling effects in tumor progression. Our study offers insight into the molecular mechanisms underlying IL-17 activities in cancer and lays the groundwork for developing personalized immunotherapies.

CD39 expression by regulatory T cells drives CD8+ T cell suppression during experimental Trypanosoma cruzi infection.

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a critical role during the initial stages after T. cruzi infection, subsequently influencing CD8+ T cells. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell responses. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, leading to improved parasite control during T. cruzi infection. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

Tofacitinib treatment of rheumatoid arthritis increases senescent T cell frequency in patients and limits T cell function in vitro.

Unraveling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms' role in treatment efficacy and side effects. Given the critical role of cellular immunity in RA pathogenesis, we sought to identify T-cell profiles characterizing RA patients under specific treatments. We compared 75 immunophenotypic and biochemical variables in healthy donors (HD) and RA patients, including those receiving different treatments as well as treatment-free patients. Additionally, we conducted in vitro experiments to evaluate the direct effect of tofacitinib on purified naïve and memory CD4+ and CD8+ T cells. Multivariate analysis revealed that tofacitinib-treated patients segregated from HD at the expense of T-cell activation, differentiation, and effector function-related variables. Additionally, tofacitinib led to an accumulation of peripheral senescent memory CD4+ and CD8+ T cells. In vitro, tofacitinib impaired the activation, proliferation, and effector molecules expression and triggered senescence pathways in T-cell subsets upon TCR-engagement, with the most significant impact on memory CD8+ T cells. Our findings suggest that tofacitinib may activate immunosenescence pathways while simultaneously inhibiting effector functions in T cells, both effects likely contributing to the high clinical success and reported side effects of this JAK inhibitor in RA.

Dynamics of circulating follicular helper T cell subsets and follicular regulatory T cells in rheumatoid arthritis patients according to HLA-DRB1 locus.

B cells, follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are part of a circuit that may play a role in the development or progression of rheumatoid arthritis (RA). With the aim of providing further insight into this topic, here we evaluated the frequency of different subsets of Tfh and Tfr in untreated and long-term treated RA patients from a cohort of Argentina, and their potential association with particular human leukocyte antigen (HLA) class-II variants and disease activity. We observed that the frequency of total Tfh cells as well as of particular Tfh subsets and Tfr cells were increased in seropositive untreated RA patients. Interestingly, when analyzing paired samples, the frequency of Tfh cells was reduced in synovial fluid compared to peripheral blood, while Tfr cells levels were similar in both biological fluids. After treatment, a decrease in the CCR7loPD1hi Tfh subset and an increase in the frequency of Tfr cells was observed in blood. In comparison to healthy donors, seropositive patients with moderate and high disease activity exhibited higher frequency of Tfh cells while seropositive patients with low disease activity presented higher Tfr cell frequency. Finally, we observed that HLA-DRB1*09 presence correlated with higher frequency of Tfh and Tfr cells, while HLA-DRB1*04 was associated with increased Tfr cell frequency. Together, our results increase our knowledge about the dynamics of Tfh and Tfr cell subsets in RA, showing that this is altered after treatment.

Extrafollicular Plasmablasts Present in the Acute Phase of Infections Express High Levels of PD-L1 and Are Able to Limit T Cell Response.

During infections with protozoan parasites or some viruses, T cell immunosuppression is generated simultaneously with a high B cell activation. It has been described that, as well as producing antibodies, plasmablasts, the differentiation product of activated B cells, can condition the development of protective immunity in infections. Here, we show that, in T. cruzi infection, all the plasmablasts detected during the acute phase of the infection had higher surface expression of PD-L1 than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in a BCR-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection expressed PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. In vitro experiments showed that PD-L1hi plasmablasts suppressed the T cell response, partially via PD-L1. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, whose peaks of response precede the peak of germinal center response, may have a modulatory function in infections, thus influencing T cell response.

Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients.

Senescent T cells have been described during aging, chronic infections, and cancer; however, a comprehensive study of the phenotype, function, and transcriptional program of this T cell population in breast cancer (BC) patients is missing. Compared to healthy donors (HDs), BC patients exhibit an accumulation of KLRG-1+CD57+ CD4+ and CD8+ T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes. KLRG-1+CD57+ CD4+ and CD8+ T cells from BC patients and HDs exhibit features of senescence, and despite their inhibitory receptor expression, they produce more effector cytokines and exhibit higher expression of Perforin, Granzyme B, and CD107a than non-senescent subsets. When compared to blood counterparts, tumor-infiltrating senescent CD4+ T cells show similar surface phenotype but reduced cytokine production. Transcriptional profiling of senescent CD4+ T cells from the peripheral blood of BC patients reveals enrichment in genes associated with NK or CD8+-mediated cytotoxicity, TCR-mediated stimulation, and cell exhaustion compared to non-senescent T cells. Comparison of the transcriptional profile of senescent CD4+ T cells from peripheral blood of BC patients with those of HDs highlighted marked similarities but also relevant differences. Senescent CD4+ T cells from BC patients show enrichment in T-cell signaling, processes involved in DNA replication, p53 pathways, oncogene-induced senescence, among others compared to their counterparts in HDs. High gene expression of CD4, KLRG-1, and B3GAT1 (CD57), which correlates with increased overall survival for BC patients, underscores the usefulness of the evaluation of the frequency of senescent CD4+ T cells as a biomarker in the follow-up of patients.

CD8+ T Cell Immunity Is Compromised by Anti-CD20 Treatment and Rescued by Interleukin-17A.

Treatment with anti-CD20, used in many diseases in which B cells play a pathogenic role, has been associated with susceptibility to intracellular infections. Here, we studied the effect of anti-CD20 injection on CD8+ T cell immunity using an experimental model of Trypanosoma cruzi infection, in which CD8+ T cells play a pivotal role. C57BL/6 mice were treated with anti-CD20 for B cell depletion prior to T. cruzi infection. Infected anti-CD20-treated mice exhibited a CD8+ T cell response with a conserved expansion phase followed by an early contraction, resulting in a strong reduction in total and parasite-specific CD8+ T cell numbers at 20 days postinfection. Anti-CD20 injection increased the frequency of apoptotic CD8+ T cells, decreased the number of effector and memory CD8+ T cells, and reduced the frequency of proliferating and cytokine-producing CD8+ T cells. Accordingly, infected anti-CD20-treated mice presented lower cytotoxicity of T. cruzi peptide-pulsed target cells in vivo All of these alterations in CD8+ T cell immunity were associated with increased tissue parasitism. Anti-CD20 injection also dampened the CD8+ T cell response, when this had already been generated, indicating that B cells were involved in the maintenance rather than the induction of CD8+ T cell immunity. Anti-CD20 injection also resulted in a marked reduction in the frequency of interleukin-6 (IL-6)- and IL-17A-producing cells, and recombinant IL-17A (rIL-17A) injection partially restored the CD8+ T cell response in infected anti-CD20-treated mice. Thus, anti-CD20 reduced CD8+ T cell immunity, and IL-17A is a candidate for rescuing deficient responses either directly or indirectly.IMPORTANCE Monoclonal antibody targeting the CD20 antigen on B cells is used to treat the majority of non-Hodgkin lymphoma patients and some autoimmune disorders. This therapy generates adverse effects, notably opportunistic infections and activation of viruses from latency. Here, using the infection murine model with the intracellular parasite Trypanosoma cruzi, we report that anti-CD20 treatment affects not only B cell responses but also CD8+ T cell responses, representing the most important immune effectors involved in control of intracellular pathogens. Anti-CD20 treatment, directly or indirectly, affects cytotoxic T cell number and function, and this deficient response was rescued by the cytokine IL-17A. The identification of IL-17A as the cytokine capable of reversing the poor response of CD8+ T cells provides information about a potential therapeutic treatment aimed at enhancing defective immunity induced by B cell depletion.

Understanding CD8+ T Cell Immunity to Trypanosoma cruzi and How to Improve It.

The protozoan Trypanosoma cruzi is the causative agent of Chagas' disease, endemic in Latin America but present worldwide. Research efforts have focused on the examination of immune mechanisms that mediate host protection as well as immunopathology during this parasitic infection. The study of CD8+ T cell immunity emerges as a key aspect given the critical importance of parasite-specific CD8+ T cells for host resistance throughout the infection. In recent years, new research has shed light on novel pathways that modulate the induction, maintenance, and regulation of CD8+ T cell responses to T. cruzi. This new knowledge is setting the ground for future vaccines and/or immunotherapies. Herein, we critically review and analyze the latest results published in the field.

Limited Foxp3+ Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8+ T Cell Immunity.

While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance.

PD-L1+ Regulatory B Cells Are Significantly Decreased in Rheumatoid Arthritis Patients and Increase After Successful Treatment.

Background: B cells play an important role in the development and maintenance of rheumatoid arthritis (RA). Although IL-10-producing B cells represent a major subset of regulatory B cells (Bregs) able to suppress autoimmune and inflammatory responses, recent reports showed that B cell-mediated immune suppression may also occur independent of IL-10. For instance, B cells can modulate T cell immune responses through the expression of regulatory molecules such as PD-L1. So far, PD-L1-expressing B cells have not been analyzed in RA patients. Objective: To analyze the frequency of PD-L1-expressing B cells in the peripheral blood of RA patients compared to healthy controls (HC) matched for sex and age, their function on T cell response and their changes in response to therapy. Methods: Fresh peripheral blood B cells from RA patients and HC were characterized by flow cytometry and their functionality assessed in a co-culture system with autologous T cells. Results: The frequencies of CD19+PD-L1+ B cells, CD24hiCD38-PD-L1+ and CD24hiCD38hiPD-L1+ B cells were significantly lower in untreated RA patients than in HC. In a follow-up study, the frequencies of PD-L1+ B cells (CD19+PD-L1+ B cells, CD24hiCD38-PD-L1+ and CD24hiCD38hiPD-L1+ B cells) increased significantly after treatment in good responder patients, although the frequency of total CD24hiCD38hi B cells decreased. CD19+ B cells from untreated RA patients and HC upregulated PD-L1 expression similarly upon stimulation with CpG plus IL-2 and were able to suppress, in vitro, CD8+ T cell proliferation and cytokine production in a PD-L1-dependent manner. Conclusions: Our results show that PD-L1+ B cells exhibiting T cell suppressive capacity are significantly decreased in untreated RA patients but increase in response to successful treatment. PD-L1 expression on B cells from RA patients can be modulated in vitro and PD-L1+ B cells could thus provide new perspectives for future treatment strategies.

IL-17RA-Signaling Modulates CD8+ T Cell Survival and Exhaustion During Trypanosoma cruzi Infection.

The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.

Inhibitory Receptor Expression on T Cells as a Marker of Disease Activity and Target to Regulate Effector Cellular Responses in Rheumatoid Arthritis.

OBJECTIVE: Inhibitory receptors are essential for the regulation of effector immune responses and may play critical roles in autoimmune diseases. We evaluated whether inhibitory receptor expression on T cells from patients with rheumatoid arthritis (RA) were correlated with immune activation, disease activity, and response to treatment, as well as whether inhibitory receptor-mediated pathways were functional. METHODS: Using flow cytometry, we performed extensive phenotypic and functional evaluation of CD4+ and CD8+ T cells from the blood and synovial fluid (SF) of RA patients ex vivo and after culture. The relationship of each parameter with the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) and response to treatment was examined. RESULTS: In RA patients with low levels of T cell activation, inhibitory receptor expression showed an inverse relationship with the DAS28-ESR. The frequency of T cells expressing multiple inhibitory receptors was reduced in untreated RA patients but returned to normal levels in treated patients. RA patients who responded to treatment showed an augmented frequency of inhibitory receptor-expressing T cells that correlated with reduced inflammatory cytokine production in comparison to nonresponders. Higher frequencies of effector and memory T cells that expressed multiple inhibitory receptors were seen in SF than in peripheral blood. Notably, inhibitory pathways were operative in blood and synovial T cells from all RA patients, although cells from nonresponder patients were less sensitive to inhibition. CONCLUSION: Inhibitory receptor expression on T cells from RA patients is inversely correlated with effector T cell function and disease activity and may predict response to treatment. Furthermore, different inhibitory pathways are functional and cooperatively suppress synovial T cells, providing a rationale for new treatment strategies to regulate acute local inflammation.

CD39 Expression Defines Cell Exhaustion in Tumor-Infiltrating CD8+ T Cells.

The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNγ production by responder CD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induce CD39 on human CD8+ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8+ T cells, with implications for defining a biomarker of T-cell dysfunction and a target for immunotherapeutic intervention.Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8+ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function. Cancer Res; 78(1); 115-28. ©2017 AACR.

Unconventional Pro-inflammatory CD4+ T Cell Response in B Cell-Deficient Mice Infected with Trypanosoma cruzi.

Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America but has become a global public health concern by migration of infected people. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to tissue injury and organ dysfunction. Here, we report the importance of B cells in conditioning T cell response in T. cruzi infection. Mice deficient in mature B cells (muMT mice) infected with T. cruzi exhibited an increase in plasma TNF concentration, TNF-producing CD4+ T cells, and mortality. The increase in TNF-producing CD4+ T cells was accompanied by a reduction in IFNγ+CD4+ T cells and a decrease of the frequency of regulatory Foxp3+, IL-10+, and IL17+CD4+ T cells populations. The CD4+ T cell population activated by T. cruzi infection, in absence of mature B cells, had a high frequency of Ly6C+ cells and showed a lower expression of inhibitory molecules such as CTLA-4, PD-1, and LAG3. CD4+ T cells from infected muMT mice presented a high frequency of CD62LhiCD44- cells, which is commonly associated with a naïve phenotype. Through transfer experiments we demonstrated that CD4+ T cells from infected muMT mice were able to condition the CD4+ T cells response from infected wild-type mice. Interestingly, using Blimp-flox/flox-CD23icre mice we observed that in absence of plasmablast/plasma cell T. cruzi-infected mice exhibited a higher number of TNF-producing CD4+ T cells. Our results showed that the absence of B cells during T. cruzi infection affected the T cell response at different levels and generated a favorable scenario for unconventional activation of CD4+ T cell leading to an uncontrolled effector response and inflammation. The product of B cell differentiation, the plasmablast/plasma cells, could be able to regulate TNF-producing CD4+ T cells since their absence favor the increase of the number of TNF+ CD4+ in T. cruzi-infected mice.

The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production.

The term regulatory B cells (B regs) is ascribed to a heterogeneous population of B cells with the function of suppressing inflammatory responses. They have been described mainly during the last decade in the context of different immune-mediated diseases. Most of the work on B regs has been focused on IL-10-producing B cells. However, B cells can exert regulatory functions independently of IL-10 production. Here we discuss the phenotypes, development and effector mechanisms of B regs and advances in their role in autoimmunity, infections and cancer.

FcγRIIb and BAFF differentially regulate peritoneal B1 cell survival.

B1 cells produce most natural Abs in unimmunized mice and play a key role in the response to thymus-independent Ags and microbial infection. Enlargement of B1 cell number in mice is often associated with autoimmunity. However, the factors that control peripheral B1 cell survival remain poorly characterized. Mice lacking the inhibitory receptor FcγRIIb exhibit a massive expansion in peritoneal B1 cells, implicating this receptor in B1 cell homeostasis. In this study, we show that peritoneal B1 cells express the highest levels of FcγRIIb among B cell subsets and are highly susceptible to FcγRIIb-mediated apoptosis. B1 cells upregulate FcγRIIb in response to innate signals, including CpG, and the B cell homeostatic cytokine BAFF efficiently protects activated B1 cells from FcγRIIb-mediated apoptosis via receptor downregulation. BAFF-transgenic mice manifest an expansion of peritoneal B1 cells that express lower levels of FcγRIIb and exhibit reduced susceptibility to apoptosis. Whereas both peritoneal B1 cells from wild-type and BAFF-transgenic mice immunized with CpG exhibit an increase in FcγRIIb levels, this change is blunted in BAFF-transgenic animals. Our combined results demonstrate that FcγRIIb controls peritoneal B1 cell survival and this program can be modulated by the BAFF signaling axis.

B-Cell Response during Protozoan Parasite Infections.

In this review, we discuss how protozoan parasites alter immature and mature B cell compartment. B1 and marginal zone (MZ) B cells, considered innate like B cells, are activated during protozoan parasite infections, and they generate short lived plasma cells providing a prompt antibody source. In addition, protozoan infections induce massive B cell response with polyclonal activation that leads to hypergammaglobulnemia with serum antibodies specific for the parasites and self and/or non related antigens. To protect themselves, the parasites have evolved unique ways to evade B cell immune responses inducing apoptosis of MZ and conventional mature B cells. As a consequence of the parasite induced-apoptosis, the early IgM response and an already establish humoral immunity are affected during the protozoan parasite infection. Moreover, some trypanosomatides trigger bone marrow immature B cell apoptosis, influencing the generation of new mature B cells. Simultaneously with their ability to release antibodies, B cells produce cytokines/quemokines that influence the characteristic of cellular immune response and consequently the progression of parasite infections.