Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Abstract

To better apprehend γ/δ T cell biological functions in the periphery, it appears crucial to identify markers highlighting the existence of distinct phenotypic and functional γ/δ T cell subsets. Interestingly, the expression of CD44 and Ly-6C subdivides murine peripheral γ/δ T cells into several subsets, with Ly-6C− CD44hi γ/δ T cells corresponding to the IL-17–producing CD27− γ/δ T cell subset exhibiting innate-like features. By comparing the other subsets to naive and memory CD8+ α/β T cells, in this study, we show that Ly-6C− or + CD44lo and Ly-6C+CD44hi γ/δ T cells greatly resemble, and behave like, their CD8+ α/β T cell counterparts. First, like memory CD8+ α/β T cells, Ly-6C+CD44hi γ/δ T cells are sparse in the thymus but largely increased in proportion in tissues. Second, similarly to naive CD8 α/β T cells, CD44lo γ/δ T cells are poorly cycling in vivo in the steady state, and their proportion declines with age in secondary lymphoid organs. Third, CD44lo γ/δ T cells undergo spontaneous proliferation and convert to a memory-like Ly-6C+CD44hi phenotype in response to lymphopenia. Finally, CD44lo γ/δ T cells have an intrinsic high plasticity as, upon appropriate stimulation, they are capable of differentiating nonetheless into Th17-like and Th1-like cells but also into fully functional Foxp3+ induced regulatory T cell–like γ/δ T cells. Thus, peripheral CD27+ γ/δ T cells, commonly considered as a functionally related T cell compartment, actually share many common features with adaptive α/β T cells, as both lineages include naive-like and memory-like lymphocytes with distinct phenotypic, functional, and homeostatic characteristics.