Advances and challenges in identifying precursors of memory CD4⁺ T cells

Memory T (T_M) cells play critical roles in protective immunity and immunopathology, and their generation and maintenance have attracted a lot of interests. In recent decades, informative investigations into CD8⁺ T_M cell precursors have greatly enhanced our understanding of fate decision during CD8⁺ T_M cell differentiation. Yet, much less is known about the generation of CD4⁺ T_M cells and their precursors. In this review, we present advances in identifying precursors of CD4⁺ T_M cells under Th1, Th2 and Th17 conditions, as well as current understanding of how intrinsic factors, extrinsic factors and positioning profiles contribute to determining fate choices of CD4⁺ T cells between effector and memory. However, the path toward a general theory of CD4⁺ T_M cell generation has been hindered by technological limitations and diversity and plasticity of CD4⁺ T subsets at effector and memory phases. We thoroughly discuss the differences and similarities in differentiation of CD4⁺ T_M cells under Th1, Th2, and Th17 conditions, and explore the prospects for identifying common precursors of specific CD4⁺ T_M cells under various types of infections and exposures.