γδ T Cells Recognize a Microbial Encoded B Cell Antigen to Initiate a Rapid Antigen-Specific Interleukin-17 Response

Abstract

Summary γδ T cells contribute uniquely to host immune defense. However, how they function remains an enigma. Although it is unclear what most γδ T cells recognize, common dogma asserts that they recognize self-antigens. While they are the major initial Interleukin-17 (IL-17) producers in infections, it is unclear what is required to trigger these cells to act. Here, we report that a noted B cell antigen, the algae protein-phycoerythrin (PE) is an antigen for murine and human γδ T cells. PE also stained specific bovine γδ T cells. Employing this specificity, we demonstrated that antigen recognition, but not extensive clonal expansion, was required to activate naïve γδ T cells to make IL-17. In this activated state, γδ T cells gained the ability to respond to cytokine signals that perpetuated the IL-17 production. These results underscore the adaptability of lymphocyte antigen receptors and suggest a previously unrecognized antigen-driven rapid response in protective immunity prior to the maturation of classical adaptive immunity.

IFN-γ–Producing and IL-17–Producing γδ T Cells Differentiate at Distinct Developmental Stages in Murine Fetal Thymus

“…Intriguingly, DN3 cells expressed Bcl11b but lost the potential to develop IL-17-producing gd T cells (9, 10), suggesting the presence of an as yet unknown suppressive mechanism. Furthermore, a recent study showed that some gd T cells migrated to the peripheral tissues as naive cells and functionally differentiated to IL-17 producers after Ag encounter (44). It remains unclear whether the development of Aginduced IL-17-producing gd T cells from naive cells requires Bcl11b.…”

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…‘natural’ γδ 17 cells (V γ 6 + and part of V γ 4 + ) developed before birth acquire interleukin‐17 ( IL ‐17) ‐producing ability in thymus and produce IL ‐17 stimulated by IL ‐1 β and IL ‐23 in the periphery. Conversely, IL ‐17 production induced by TCR signalling was also reported 56. Naive γδ T cells developed after birth may egress the thymus as ‘inducible’ γδ 17 cells (mostly V γ 4 + ) and differentiate to produce IL ‐17 after encounter with antigen.…”

“…Although γδ 17 cells typically behave as innate‐like immune cells, IL‐17 induction by TCR signalling is also reported. Mouse and human γδ T cells recognize an algal protein, phycoerythrin, and differentiate to IL‐17‐producing cells after immunization by this antigen 56. These studies, in combination with cell reconstitution studies,50 suggest that ‘natural’ γδ 17 cells (V γ 6 + and part of V γ 4 + ) acquire IL‐17‐producing ability in the fetal thymus and do not require TCR stimulation in the periphery, whereas ‘inducible’ γδ 17 cells (mostly V γ 4 + ) that develop after birth produce IL‐17 upon encounter with antigens57 (Fig.…”

“…1). Notably, phycoerythrin antigen stimulation induces IL‐1R expression on γδ T cells 56. Therefore, γδ TCR activation may make ‘inducible’ γδ 17 cells respond to IL‐1 β and IL‐23 to induce IL‐17.…”

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…In contrast to conventional αβ T cells, γδ T cells are not dependent on classical MHC molecules presenting peptides. Based on the ligands that have been identified, it appears that some γδ TCRs can recognize antigens in an antibody-like fashion, whereas the TCRs of other γδ T-cell subsets can bind to nonclassical MHC-I or MHClike proteins (2,(5)(6)(7)(8)(9)(10)(11). Although there are common characteristics among γδ T cells, some of which are shared with VLRC + cells (4), it is clear that γδ T cells do not represent a homogenous population of cells with a single physiological role (12).…”