Multifunctional immune responses of HMBPP-specific Vγ2Vδ2 T cells in M. tuberculosis and other infections

Abstract

Vγ2Vδ2 T (also known as Vγ9Vδ2 T) cells exist only in primates, and in humans represent a major γδ T-cell sub-population in the total population of circulating γδ T cells. Results from recent studies suggest that while (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen from Mycobacterium tuberculosis (Mtb) and other microbes activates and expands primate Vγ2Vδ2 T cells, the Vγ2Vδ2 T-cell receptor (TCR) recognizes and binds to HMBPP on antigen-presenting cells (APC). In response to HMBPP stimulus, Vγ2Vδ2 TCRs array to form signaling-related nanoclusters or nanodomains during the activation of Vγ2Vδ2 T cells. Primary infections with HMBPP-producing pathogens drive the evolution of multieffector functional responses in Vγ2Vδ2 T cells, although Vγ2Vδ2 T cells display different patterns of responses during the acute and chronic phases of Mtb infection and in other infections. Expanded Vγ2Vδ2 T cells in primary Mtb infection can exhibit a broader TCR repertoire and a greater clonal response than previously assumed, with different distribution patterns of Vγ2Vδ2 T-cell clones in lymphoid and non-lymphoid compartments. Emerging in vivo data suggest that HMBPP activation of Vγ2Vδ2 T cells appears to impact other immune cells during infection.

Figure 1

Immune responses and functions of HMBPP-specific Vγ2Vδ2 T cells in infections. Shown are drawings describing the following immune events: (i) Vγ2Vδ2 TCR recognition of HMBPP phosphoantigen on the APC surface; (ii) innate immune responses of HMBPP-activated Vγ2Vδ2 T cells; (iii) clonal expansion of Vγ2Vδ2 T cells in response to signals from HMBPP/TCR and cytokines; (iv) trafficking of Vγ2Vδ2 T cells to lungs or mucosal surfaces; (v) evolving T effector functions of producing/coproducing cytokines; (vi) anti-TB or anti-Listeria activities of Vγ2Vδ2 T cells in vitro; (vii) potential in vivo functions of Vγ2Vδ2 T cells against TB; (viii) immune enhancing function of Vγ2Vδ2 T cells. APC, antigen-presenting cell; HMBBP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; TB, tuberculosis; TCR, T-cell receptor.