Distinct Cytokine-Driven Responses of Activated Blood γδ T Cells: Insights into Unconventional T Cell Pleiotropy

Abstract

Human Vγ9/Vδ2 T cells comprise a small population of peripheral blood T cells that in many infectious diseases respond to the microbial metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), expanding to up to 50% of CD3+ cells. This “transitional response,” occurring temporally between the rapid innate and slower adaptive response, is widely viewed as proinflammatory and/or cytolytic. However, increasing evidence that different cytokines drive widely different effector functions in αβ T cells provoked us to apply cDNA microarrays to explore the potential pleiotropy of HMB-PP-activated Vγ9/Vδ2 T cells. The data and accompanying validations show that the related cytokines, IL-2, IL-4, or IL-21, each drive proliferation and comparable CD69 up-regulation but induce distinct effector responses that differ from prototypic αβ T cell responses. For example, the Th1-like response to IL-2 also includes expression of IL-5 and IL-13 that conversely are not induced by IL-4. The data identify specific molecules that may mediate γδ T cell effects. Thus, IL-21 induces a lymphoid-homing phenotype and high, unexpected expression of the follicular B cell-attracting chemokine CXCL13/BCA-1, suggesting a novel follicular B-helper-like T cell that may play a hitherto underappreciated role in humoral immunity early in infection. Such broad plasticity emphasizes the capacity of γδ T cells to influence the nature of the immune response to different challenges and has implications for the ongoing clinical application of cytokines together with Vγ9/Vδ2 TCR agonists.

Cross-presenting human γδ T cells induce robust CD8 + αβ T cell responses

“…Responses of V␥9V␦2 ϩ T cells to HMB-PP and related compounds are both rapid and vigorous (25) and, thus, are reminiscent of cellular responses mediated by receptors for pathogenassociated molecular patterns. It is not known how V␥9V␦2 ϩ T cells recognize these nonpeptide agonists and whether TCR triggering requires the presentation of such compounds by specialized ''feeder cells.''…”

“…Importantly, transition from resting to fully activated V␥9V␦2 ϩ T cells (termed ␥␦ T-APCs) is associated with the expression of CCR7 that enables lymph node homing and a plethora of antigen-presentation and costimulation molecules (10,26). It is uncertain where in the human body antigen presentation by ␥␦ T-APCs may take place, but possible sites include the site of microbial encounter in peripheral tissues and infection draining lymphoid tissues (9,10,25,(27)(28)(29).…”

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Depending on the culture conditions, Vc9/Vd2 T cells clearly assume different functions including distinct cytokine profiles [49,74,72,[124][125][126], and hence more research is needed to delineate whether Vc9/Vd2 T-APCs may induce different 'flavors' of CD4 + T cell responses (Th1, Th2, Th17, Th22, Treg), and what the signals involved in such a polarization are. In this respect, our preliminary findings suggest that under appropriate conditions Vc9/Vd2 T-APCs are able to induce considerable IL-22 expression in naive CD4 + T cells [C.J.T., M.E.…”

“…While Vc9/Vd2 T cells are typically portrayed as pro-inflammatory [70] they nevertheless co-express factors such as IL-4 [71][72][73][74]. Indeed, most effects of Vc9/Vd2 T cells on monocytes are largely mediated via IFN-c and TNF-a as well as GM-CSF, yet IL-4 may make an additional contribution to shaping the phenotype and function of Vc9/Vd2 T cell-triggered inflammatory DCs [61].…”

“…Indeed, microarray studies revealed that Vc9/Vd2 T cells primed in the presence of IL-21 assume features typically associated with human T FH cells, most notably the expression of the B cell attracting chemokine, CXCL13, which is key in recruiting B cells to secondary lymphoid tissue and establishing germinal centers [74]. On a functional level, activated Vc9/Vd2 T cells readily provide B cell help in vitro, with a particular contribution of Vc9/Vd2 T cell-expressed CD40L and inducible T cell co-stimulator (ICOS) as well as IL-4 and IL-10 [111,112].…”