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

To better apprehend gamma/delta T cell biological functions in the periphery, it appears crucial to identify markers highlighting the existence of distinct phenotypic and functional gamma/delta T cell subsets. Interestingly, the expression of CD44 and Ly-6C subdivides murine peripheral gamma/delta T cells into several subsets, with Ly-6C(-) CD44 hi gamma/delta T cells corresponding to the IL-17-producing CD27(-) gamma/delta T cell subset exhibiting innate-like features. By comparing the other subsets to naive and memory CD8(+) alpha/beta T cells, in this study, we show that Ly-6C(-) (or) (+) CD44(lo) and Ly-6C(+) CD44 hi gamma/delta T cells greatly resemble, and behave like, their CD8(+) alpha/beta T cell counterparts. First, like memory CD8(+) alpha/beta T cells, Ly-6C(+) CD44 hi gamma/delta T cells are sparse in the thymus but largely increased in proportion in tissues. Second, similarly to naive CD8 alpha/beta T cells, CD44(lo) gamma/delta T cells are poorly cycling in vivo in the steady state, and their proportion declines with age in secondary lymphoid organs. Third, CD44(lo) gamma/delta T cells undergo spontaneous proliferation and convert to a memory-like Ly-6C(+) CD44 hi phenotype in response to lymphopenia. Finally, CD44(lo) gamma/delta 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 gamma/delta T cells. Thus, peripheral CD27(+) gamma/delta T cells, commonly considered as a functionally related T cell compartment, actually share many common features with adaptive alpha/beta T cells, as both lineages include naive-like and memory-like lymphocytes with distinct phenotypic, functional, and homeostatic characteristics.