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

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.

“An Intrinsic Program Determines Key Age-Associated Changes in Adaptive Immunity That Limit Response to Non-Pathogens”

“…In the aged, there is a dramatic loss of naïve CD4 (and CD8) T cell number and repertoire due in part due to reduced production of naïve T cells. In response, the naïve T cell population decreases and cells with altered phenotype appear, perhaps driven by constitutive "homeostatic" cytokines that drive their homeostasis (Cicin-Sain et al, 2007;Kawabe et al, 2020).…”

“…As the naïve T cell population becomes smaller with age, the memory population, defined most often by high CD44 expression expands (Cicin-Sain et al, 2007;Kawabe et al, 2020). In freeliving populations exposed to many sources of foreign antigens, including microbial pathogens and commensal organisms, it makes sense that conventional memory cells accumulate over time.…”

“…Thus, it was initially surprising that T cells with a "memory phenotype" increase with age in unimmunized inbred laboratory animals kept in specific pathogen-free (SPF) conditions (Surh and Sprent, 2008;Chiu et al, 2013;Nikolich-Žugich, 2018). Moreover, CD8 and CD4 T cells of memory phenotype accumulate in germfree (GF) mice not exposed to foreign or commensal microbes, and even in GF mice on elemental diets that lack food antigens (Pereira et al, 1986;Dobber et al, 1992;Haluszczak et al, 2009;White et al, 2017;Kawabe et al, 2020). The "memory phenotype" CD8 T cells express CD44, the "signature" memory cell marker, as well as elevated adhesion molecules (CD18, CD49d), activation-associated molecules (CD69), and survival cytokine receptors (CD122, CD132).…”

Global Gene Expression of T Cells Is Differentially Regulated by Peritoneal Dendritic Cell Subsets in an IL-2 Dependent Manner

“…Recent studies on the cytokine milieus that lead the differentiation of T cells into specific subsets indicated that DCs actively take part in generating such conditions. DCs can directly secrete certain cytokines and/or modulate the response to specific cytokines (22,23). DCs can also indirectly regulate the level of particular cytokines by inducing T cells to secrete and/or to consume those cytokines (21,22).…”

“…Therefore, the regulation of IL-2 in the milieu is important in dictating the fate of T cells. Although it is believed that DCs have an important role in modulating various cytokines in the milieu and thus regulating the outcome of T cell responses (21)(22)(23), it has remained poorly understood how and which DC subsets are involved in controlling IL-2 in the milieu.…”