Foreign antigen-independent memory-phenotype CD4⁺ T cells: a new player in innate immunity?

In an Opinion article published in May 2017 (Antigen-inexperienced memory CD8⁺ T cells: where they come from and why we need them. Nat. Rev. Immunol. 17, 391–400 (2017)¹), Ross Kedl and colleagues provided a comprehensive review concerning foreign antigen-inexperienced CD8⁺ T lymphocytes with a memory phenotype (MP). This population develops without foreign antigen recognition and consists of thymus-derived innate memory (T_IM) and peripherally generated virtual memory (T_VM) cells. Importantly, these CD8⁺ MP lymphocyte subsets exert innate effector function in terms of cytokine production² and/or host resistance to infection in vivo³.

From available evidence, these authors argued that CD4⁺ T cells fail to generate a corresponding foreign antigen-independent MP population in lymphoreplete mice while likely doing so in humans¹. They based this hypothesis in part on the observations that most murine CD44^hi CD4⁺ T cells are CD49d⁺ (a marker for antigen-specific effector and/or memory CD8⁺ T cells)⁴, and that CD44^hi CD4⁺ T cells are virtually absent in T cell receptor (TCR)-transgenic Rag-deficient mice in steady state⁵.

Nevertheless, the late Charles Surh and colleagues demonstrated the existence of CD4⁺ T cells with a MP (CD44^hi CD62L^lo) in mice and, importantly, showed that this population is present equally in specific-pathogen-free, germ-free, and antigen-free mice⁶. As antigen-free mice are germ-free animals raised on an elemental diet free of potential food antigens and thus unexposed to virtually all foreign antigens, self-reactivity may serve as a key driving factor in the development of MP CD4⁺ T lymphocytes in a lymphoreplete environment, although commensal antigen recognition may contribute to the generation of these cells in lymphopenic settings^7,8. Moreover, distinct from typical memory CD4⁺ T cells, CD4⁺ MP cells rapidly proliferate under steady-state conditions⁹. We suggest that MP CD4⁺ T cells were not detected in TCR-transgenic Rag-deficient mice because they possess an overabundance of cells showing homogeneous expression of a TCR with low affinity for self-antigens; consequently, these cells may out-compete those precursors that would normally differentiate into MP cells during homeostatic proliferation.

Recently, we have found that in a lymphoreplete environment MP CD4⁺ T cells are spontaneously generated from peripheral naive T cell precursors and in particular from those expressing high levels of CD5 (Ref. 10), a reliable marker for self reactivity¹¹. In the steady state, the CD4⁺ MP population consists of both T-bet^hi and T-bet^low subsets, the former of which differentiates as a consequence of tonic IL-12 signalling acting through a T-bet-dependent positive feedback loop. Importantly, in infectious settings, these T-bet^hi MP cells produce IFNγ in response to pathogen-induced IL-12 in the absence of foreign antigen recognition and thereby contribute to innate resistance and enhancement of T helper1 (T_H1)-type effector immunity. Thus, the T-bet^hi CD4⁺ MP subset can be seen as a continuously generated lymphocyte population that provides an additional layer of innate immunity beyond that provided by CD8⁺ T_IM and T_VM cells, natural killer cells, natural killer T cells, and innate lymphoid cells.

We propose that spontaneous acquisition of a memory-like phenotype associated with innate immune function is a feature of both CD4⁺ and CD8⁺ T lymphocytes, although T_IM cells are restricted to the CD8⁺ T cell lineage. As TCR-bearing T cells that possess innate activity, MP cells present a striking example of the intersection of the innate and adaptive immune systems.