Requirements for the differentiation of innate T-bethigh memory-phenotype CD4+ T lymphocytes under steady state

Takeshi Kawabe,Alan Sher,Dragana Jankovic,Jaeu Yi,Hidehiro Yamane,Difeng Fang,Naoto Ishii,Akihisa Kawajiri,Giorgio Trinchieri,Jinfang Zhu,Kerry Hilligan,Kwang Soon Kim

doi:10.1038/s41467-020-17136-1

Abstract

CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4+ T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bethigh, T-betlow, and T-bet− subsets, with innate, Th1-like effector activity exclusively associated with T-bethigh cells. We further show that the latter population depends on IL-12 produced by CD8α+ type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4+ T lymphocytes. We propose that optimal differentiation of T-bethigh MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.

Highlights

CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis
As revealed in our previous work[2], MP CD4+ T cells exist under uninfected, steady-state conditions as CD44highCD62Llow Foxp3−CD4+ αβT lymphocytes in the spleen, a major site of their generation (Fig. 1a; gating strategy is shown in Methods)
We found that in steady state, MP cells differentiate into a T-bethigh subset in the presence of IL-12 derived from DC1 endowed with an activated phenotype

Summary

Introduction

CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. Type immunity and later contribute to the development of Agspecific effector T cells[2] In this regard, we have previously shown that MP CD4+ T cells rapidly produce IFN-γ in response to Th1associated inflammatory cytokines in the absence of foreign Ag recognition and can participate in host defense against Toxoplasma infection[2]. We have previously shown that MP CD4+ T cells rapidly produce IFN-γ in response to Th1associated inflammatory cytokines in the absence of foreign Ag recognition and can participate in host defense against Toxoplasma infection[2] We proposed that this type of innate-like activity exerted by MP cells may significantly contribute to the innate immune resistance mediated by natural killer (NK) cells, innate lymphoid cells (ILCs), and virtual memory CD8+ T lymphocytes[3,4,5]. MP cells rapidly proliferate in steady state while conventional memory T lymphocytes are essentially quiescent[8], suggesting distinct mechanisms for their maintenance as well as function

Methods

Results

Conclusion