Memory-phenotype CD4⁺ T Lymphocytes: A Novel Therapeutic Target in Infectious or Autoimmune Diseases?

Infectious diseases are posing threats to the world. Although several types of antibiotics and antivirals have been created to treat the diseases, emerging/re-emerging infectious diseases, as well as those caused by pathogens with multidrug resistance, remain to be significant challenges. As a new therapeutic approach, "host-directed therapy" that enhances immune responses of host cells has been proposed. Nevertheless, the agents used in this strategy often lead to a side effect of hyperinflammation, posing a challenge in developing safe and effective drugs. In this review, I suggest boosting a novel CD4⁺ T lymphocyte population called "memory-phenotype (MP) cells" as a target of the host-directed therapy. MP cells are homeostatically generated from peripheral naïve precursors via recognition of self rather than foreign antigens and are maintained via rapid proliferation in steady state. Surprisingly, MP cells possess innate immune function; they can respond to an inflammatory cytokine IL-12 in the absence of antigen recognition to produce IFN-γ, thereby contributing to host defense against Toxoplasma and Mycobacterium. In this article, I summarize our current understanding of the mechanisms of generation, maintenance, differentiation, and innate effector function of MP CD4⁺ T lymphocytes and further discuss how we can target these cells as a new therapeutic strategy to infectious and autoimmune/inflammatory diseases.