Homeostasis and immunological function of self-driven memory-phenotype CD4⁺ T lymphocytes

CD4⁺ T lymphocytes play an essential role in adaptive immune responses. In pathogen infection, naïve CD4⁺ T cells that strongly respond to foreign antigens robustly proliferate to differentiate into effector/memory cells, contributing to elimination of the pathogen concerned. In addition to this conventional T cell activation pathway, naïve T cells can also weakly respond to self antigens in the periphery to spontaneously acquire a memory phenotype through homeostatic proliferation in steady state. Such ‘memory-phenotype’ (MP) CD4⁺ T lymphocytes are distinguishable from foreign antigen-specific memory cells in terms of marker expression. Once generated, MP cells are maintained by rapid proliferation while differentiating into the T-bet⁺ ‘MP1’ subset, with the latter response promoted by IL-12 homeostatically produced by type 1 dendritic cells. Importantly, MP1 cells possess innate immune function; they can produce IFN-γ in response to IL-12 and IL-18 to contribute to host defense against pathogens. Similarly, the presence of RORγt⁺ ‘MP17’ and Gata3^hi ‘MP2’ cells as well as their potential immune functions have been proposed. In this review, I will discuss our current understanding on the unique mechanisms of generation, maintenance, and differentiation of MP CD4⁺ T lymphocytes as well as their functional significance in various disease conditions.