Strong homeostatic TCR signals induce formation of self‐tolerant virtual memory CD8 T cells

Abstract

Virtual memory T cells are foreign antigen‐inexperienced T cells that have acquired memory‐like phenotype and constitute 10–20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen‐experienced memory T cells are incompletely understood. By analyzing T‐cell receptor repertoires and using retrogenic monoclonal T‐cell populations, we demonstrate that the virtual memory T‐cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self‐reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T‐cell compartment via modulating the self‐reactivity of individual T cells. Although virtual memory T cells descend from the highly self‐reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self‐reactivity in polyclonal T cells for the generation of functional T‐cell diversity.

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8 + T cells

“…It has been established in several independent mouse models that the quality of TCR signaling closely relates to the formation of T AIM cells (27,39,40). Our results show that loss of DOT1L leads to reduced surface expression of the CD3/TCR complex and coreceptors.…”

Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection

“…T VM emerge in naive mice with an unrestricted TCR repertoire and in response to various stimuli including IL-15, IFN-I, and IL-4 13 , 20 – 22 . While TCR involvement remains to be fully deciphered, recent data suggest that T VM are favored by stronger TCR signals against self-antigens but maintain self-tolerance 13 , 21 – 24 . Whereas T VM development in C57BL/6 mice mostly depends on IL-15, IL-4 is the main driver of T VM expansion in BALB/c mice 25 .…”

Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality

“…They are generated in neonatal mice 9,10 independently of antigen exposure, as evidenced by their presence in germ-free mice, antigen-free mice and CD8 + T cell populations specific for viral antigens in naive mice [11][12][13][14] . Common γ (γc) chain cytokine signalling is thought to drive the semidifferentiated phenotype of T VM cells, likely via homoeostatic proliferation, with IL-15 transpresentation by CD8α + dendritic cells (DCs) required for their generation 11,15 , and they appear to develop from T cells with modestly self-reactive TCRs 13,14,[16][17][18] . Although antigenically naive, T VM cells are functionally distinct from true naive T (T N ) cells, as T VM engage proliferation and cytokine production more rapidly upon TCR stimulation and can also respond to cytokine stimulation 17,19 .…”