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.

Summary For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium vs. 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 feed-forward circuit involving pro-inflammatory 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.

anti-microbial immunity ͉ antigen cross-presentation

Summary After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against re-infection. 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 re-infection. Here we show that within lymph nodes (LN), 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 following antigen recognition. These data reveal the distinct localization and dynamic behavior of naive vs. memory T cells within LN and how these differences contribute to host defense.

IntroductionThe extraordinary conservation of the subset of T cells expressing V␥V␦-T-cell receptors (TCRs) suggests a nonredundant but still poorly understood role in immune defense. [1][2][3][4][5] The 2 major ␥␦ T-cell subsets in human beings, defined by TCRs containing V␦1 or V␦2 chains, differ in their anatomic localization; V␦1 ϩ T cells predominate within mucosal epithelia and skin whereas V␦2 ϩ T cells are most numerous in peripheral blood. A function in antimicrobial immunity is supported by the dramatic expansion of human ␥␦ T cells in response to a wide range of pathogens and by reduced ␥␦ T-cell numbers and function during disease progression. 4,5 Infectious disease models demonstrated a 2-stage involvement of ␥␦ T cells, the first taking place during the innate phase of primary immune responses and the second being effective during wound repair after pathogen elimination. 4,5 Recently, ␥␦ T cells were postulated to contribute also to memory responses against mycobacteria. 6 Lysates from a large variety of bacteria, parasites, and plants were shown to induce oligoclonal expansion of human V␦2 ϩ T cells in vitro. 3,4 However, ␥␦ T cells differ fundamentally from ␣␤ T cells in the types of antigens (Ags) they recognize. Human ␥␦ T cells recognize small molecular weight nonpeptide Ags, stress-or tumor-induced self Ags, and the CD1 nonpolymorphic lipid Ag-presenting molecules. 3,4,7 The principal pathogen-derived ␥␦ T-cell Ags are isopentenyl pyrophosphate (IPP) and one of its metabolic precursors, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). [8][9][10] The "simple" mode of Ag recognition (apparent lack of requirement for Ag processing and major histocompatibility complex [MHC] restriction) and the chemical nature of these essential pathogen-specific metabolites suggest a "pattern recognition" type of Ag selectivity by human V␦2 ϩ T cells. 3,4,9 CD1-restricted Ag recognition mainly involves V␦1-TCRs and appears to participate in self-recognition of nonpolymorphic CD1 that may contribute to dendritic cell (DC) maturation 11 (M.B.B. and D. Leslie, personal written communication, July 2002).Responsiveness to microbial metabolic intermediates points to an immediate (as opposed to proliferation/differentiation-dependent) involvement of ␥␦ T cells in antimicrobial processes. Therefore, the migration properties of ␥␦ T cells may resemble those of monocytes and granulocytes that appear early at sites of infection. Chemokines are best known for controlling leukocyte localization during hematopoiesis, initiation of immune responses, and inflammation. 12-14 Traffic patterns and the inflammatory function in leukocytes are largely defined by their chemokine receptor expression and migration profile. Chemokines are divided into 2 major subfamilies, the "homeostatic" and the "inflammatory" chemokines, and their distinctive roles are best exemplified in mature T cells. [14][15][16][17][18] The homeostatic chemokines SLC/CCL21 13 and ELC/CCL19 are constitutively produced in T zones of secondary lymphoid tis...

In this study we have examined the migration responses of human peripheral blood or tonsillar B lymphocytes to a selection of 27 chemokines. Freshly isolated (CD19(+)) B lymphocytes show greatly impaired in vitro chemotaxis which is overcome by overnight culture. The best responses of cultured B lymphocytes were observed with BCA-1, SLC, ELC and SDF-1, reaching 19-26% of total input cells that have migrated, followed by LARC and TECK with 5-10% of migrated cells, whereas no other chemokine was found to be active. Stimulation of B lymphocytes with lipopolysaccharide or anti-CD40 plus IL-4 resulted in marked enhancement of the migration response to BCA-1, SLC, ELC and SDF-1, reaching 30-60% migrated cells at 12 or 36 h of culture respectively. The activation-dependent increase in the migration efficacy was transient and declined to base level responses after 72 h of culture. Under no circumstances did we detect B lymphocyte chemotaxis to inflammatory chemokines. Also, mobilization of intracellular calcium ([Ca(2+)](i)), an otherwise typical response of leukocytes to chemokines, was not observed. The transient increase in B lymphocyte migration did not correlate with changes in chemokine receptor expression, as evidenced by cell surface staining with antibodies to CXCR4, CXCR5 and CCR6, and by receptor transcript analyses. BCA-1, SLC, ELC and SDF-1 are typical 'housekeeping' chemokines with prominent expression at discrete locations in lymphoid tissues. Modulation of migration to these chemokines may be a critical mechanism for the proper positioning of B lymphocytes during humoral responses in secondary lymphoid tissues.

No abstract

Functionally naive CD8 T cells in peripheral blood from adult humans can be fully described by their CD45RAbrightCCR7+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.