A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection.

For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium versus dysregulated immunity remain unresolved. Here, we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling networks distinguished lethal from sublethal infections. Flow cytometry and gene expression analysis involving isolated cell subpopulations from infected lungs showed that neutrophil influx largely accounted for the predictive transcriptional signature. Automated imaging analysis, together with these gene expression and flow data, identified a chemokine-driven feedforward circuit involving proinflammatory neutrophils potently driven by poorly contained lethal viruses. Consistent with these data, attenuation, but not ablation, of the neutrophil-driven response increased survival without changing viral spread. These findings establish the primacy of damaging innate inflammation in at least some forms of influenza-induced lethality and provide a roadmap for the systematic dissection of infection-associated pathology.

Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node.

After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against reinfection. Recently, the spatial distribution of memory cells was found to contribute to their protective function. Effector memory CD8+ T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of reinfection. Here we show that within lymph nodes (LNs), memory CD8+ T cells were concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9-dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8+ T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed from that seen after antigen recognition. These data reveal the distinct localization and dynamic behavior of naive versus memory T cells within LNs and how these differences contribute to host defense.

Cross-presenting human gammadelta T cells induce robust CD8+ alphabeta T cell responses.

Gammadelta T cells are implicated in host defense against microbes and tumors but their mode of function remains largely unresolved. Here, we have investigated the ability of activated human Vgamma9Vdelta2(+) T cells (termed gammadelta T-APCs) to cross-present microbial and tumor antigens to CD8(+) alphabeta T cells. Although this process is thought to be mediated best by DCs, adoptive transfer of ex vivo antigen-loaded, human DCs during immunotherapy of cancer patients has shown limited success. We report that gammadelta T-APCs take up and process soluble proteins and induce proliferation, target cell killing and cytokine production responses in antigen-experienced and naïve CD8(+) alphabeta T cells. Induction of APC functions in Vgamma9Vdelta2(+) T cells was accompanied by the up-regulation of costimulatory and MHC class I molecules. In contrast, the functional predominance of the immunoproteasome was a characteristic of gammadelta T cells irrespective of their state of activation. Gammadelta T-APCs were more efficient in antigen cross-presentation than monocyte-derived DCs, which is in contrast to the strong induction of CD4(+) alphabeta T cell responses by both types of APCs. Our study reveals unexpected properties of human gammadelta T-APCs in the induction of CD8(+) alphabeta T effector cells, and justifies their further exploration in immunotherapy research.

Gammadelta T cells: an alternative type of professional APC.

A subtype of activated human gammadelta T cells, termed Vdelta2+ T cells, has antigen-presentation features similar in potency and efficacy to those seen in dendritic cells. Comparable treatment of alphabeta T cells does not result in 'professional' antigen presenting cells (APCs). What is so special about Vdelta2+ T cells? How do they acquire these unexpected properties? Under what physiological conditions would such a bridge between innate and adaptive immunity come into play? In addition to discussing these questions, we introduce a model that correlates the expression of lymph node homing receptors in Vdelta2+ T cells with the involvement of this alternative type of APC in anti-microbial alphabeta T cell responses.

Professional antigen-presentation function by human gammadelta T Cells.

Human gammadelta T cells are considered to play a vital role in protective immunity through cytokine secretion and cytotoxic activity. We report that cells expressing the Vgamma2Vdelta2+-T cell receptor (Vdelta2+ T cells) also display principal characteristics of professional antigen-presenting cells such as dendritic cells. Thus, when activated, these cells efficiently processed and displayed antigens and provided co-stimulatory signals sufficient for strong induction of naïve alphabeta T cell proliferation and differentiation. We suggest that, upon microbial activation, Vdelta2+ T cells participate in the induction of adaptive immune responses and that these cells may be a useful tool in vaccine development and immunotherapy.

Human thymus exports naive CD8 T cells that can home to nonlymphoid tissues.

Functionally naive CD8 T cells in peripheral blood from adult humans can be fully described by their CD45RA(bright)CCR7(+)CD62L(+) cell surface phenotype. Cord blood lymphocytes, from healthy newborns, are homogenously functionally naive. Accordingly, the majority of cord blood CD8 T cells express the same pattern of cell surface molecules. Unexpectedly, however, a significant fraction of cord blood CD8 T cells express neither CCR7 nor CD62L. Yet these cells remain functionally naive as they contain high levels of TCR excision circles, have long telomeres, display highly polyclonal TCRs, and do not exhibit immediate effector functions. In addition, these CD8 T cells already represent a significant fraction of the mature naive CD8 single-positive thymocyte repertoire and may selectively express the cutaneous lymphocyte Ag. We suggest that CD8 single-positive thymocytes comprise two pools of naive precursors that exhibit distinct homing properties. Once seeded in the periphery, naive CCR7(+)CD62L(+) CD8 T cells patrol secondary lymphoid organs, whereas naive CCR7(-)CD62L(-) CD8 T cells selectively migrate to peripheral tissues such as skin.

Flexible migration program regulates gamma delta T-cell involvement in humoral immunity.

gamma delta T cells are inadequately defined both in terms of their migration potential and contribution to antimicrobial immunity. Here, we have examined the migration profile of human blood gamma delta T cells and related cell lines and correlated these findings with their distribution in secondary lymphoid tissues and their function in B-cell cocultures. We find that resting gamma delta T cells are characterized by an inflammatory migration program similar to cells of the innate immune system. However, T-cell receptor (TCR) triggering resulted in the rapid but transient induction of a lymph node (LN)-homing program, as evidenced by functional CCR7 expression and concomitant reduction in expression and function of CCR5 and, to a lesser degree, CCR2. Moreover, the LN-homing program was reflected by the presence of gamma delta T cells in gastrointestinal lymphoid tissues, notably in clusters within germinal centers of B-cell follicles. In line with these findings, V gamma V delta-TCR triggering resulted in prominent expression of essential B-cell costimulatory molecules, including CD40L, OX40, CD70, and ICOS. Furthermore, gamma delta T cells were shown to provide potent B-cell help during in vitro antibody production. Collectively, our findings agree with a role for gamma delta T cells in humoral immunity during the early phase of antimicrobial responses.

Cytotoxic HIV-1 p55gag-specific CD4+ T cells produce HIV-inhibitory cytokines and chemokines.

CD4+ T-helper cells appear to be essential in sustaining immune responses in chronic viral infections, as the maintenance of CD8+ cytotoxic T-lymphocyte responses and the control of viremia were demonstrated to depend on CD4+ T cell help. In order to investigate the function of HIV-specific CD4+ T cells in chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed before and 3 and 6 months after initiation of antiviral treatment. Ten patients showed a substantial, although weak, proliferative response to HIV-1-p55gag protein for which no improvement was observed upon initiation of HAART. From one individual, HIV-1-p55gag-specific CD4-positive T-cell clones were generated that were heterogeneous in their TCR Vbeta gene usage and HLA-DRB1*13 and DRB1*03 restricted, respectively. In addition, some CD4+ TCC produced substantial amounts of IFN-gamma and MIP-1alpha/beta were perforin-positive, and showed cytotoxic activity. These diverse functional features of HIV-specific CD4+ T cells suggest that they may exert direct antiviral activity.