Memory-phenotype CD4+ T cells spontaneously generated under steady-state conditions exert innate TH1-like effector function

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Science Immunology  16 Jun 2017:
Vol. 2, Issue 12, eaam9304
DOI: 10.1126/sciimmunol.aam9304

Broadening the immune spectrum

Traditionally, the immune system has been thought to have two branches—a rapid antigen-independent innate response and a more specific antigen-dependent variable response. Kawabe et al. now add to the view that the immune response covers a broader spectrum. They found that memory-phenotype CD4+ T cells are generated from naïve T cells independently of infection, aided by environmental interleukin-12 (IL-12). These cells rapidly produced IFN-γ in response to IL-12 in the absence of pathogen recognition and provided both nonspecific defense and an adaptive immune boost against the TH1 pathogen Toxoplasma gondii. These memory-phenotype CD4+ T cells provide an early innate response, forming an additional span bridging innate and adaptive immunity.


Conventional CD4+ T cells are composed of naïve, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells under steady state. Naïve and pathogen-specific memory cells play key roles in adaptive immunity, whereas the homeostatic mechanisms regulating the generation of MP cells and their biological functions are unclear. We show that MP cells are autonomously generated from peripheral naïve cells in the absence of infectious stimulation in a T cell receptor (TCR)– and CD28-dependent manner. We further demonstrate that MP cells contain a T-bethi subpopulation that is continuously generated by environmental interleukin-12 (IL-12) and rapidly produces interferon-γ (IFN-γ) in response to IL-12 in the absence of pathogen recognition. These cells can provide nonspecific host resistance against Toxoplasma gondii infection while enhancing the adaptive CD4+ T cell responses. Together, these findings reveal that MP cells are continuously generated from naïve precursors and have a previously undescribed innate immune function by which they produce an early, T helper cell type 1 (TH1)–like protective response against pathogens.

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