A Two-Step Process of Effector Programming Governs CD4+ T Cell Fate Determination Induced by Antigenic Activation in the Steady State

Abstract

Highlights d Induction of effector precursors is inherent to T cell responses in the steady state d Effector precursors are programmed for terminal differentiation upon re-stimulation d cDC2 and functions of mTORC1 in T cells increase induction of effector precursors d Greater proportion of effector precursors decreases numbers of potential pTreg cells

Landscape of Hopx expression in cells of the immune system

“…In addition to its specific molecular functions described above, Hopx has recently emerged as a crucial marker of the specific developmental and differentiation potentials of progenitor populations in various non-hematopoietic tissues both in human and mouse systems (Mariotto et al, 2016). The most recent results now extended such capacity of Hopx also to cells of the immune cells by uncovering the key roles of Hopx in indicating specific pre-effector differentiation potentials induced early in CD4 þ T cells following their antigen-specific activation in the steady state (Opejin et al, 2020).…”

The formation of pre-effectors in the steady state opens a new perspective for cancer immunosurveillance

“…Therefore, the preferential induction of tolerance mechanisms in the steady state is not easily reconciled with a formation of specific effector T cells during immunosurveillance. However, our recently published results revealed that in addition to promoting a conversion into pTreg cells, antigen-specific activation of T cells in the steady state unlocks a much broader potential for subsequent T cell differentiation [ 13 ]. Specifically, we uncovered that in addition to the initiation of pTreg cell conversion, T cells can also become specifically “pre-committed” in the steady state to undergo Th1/Th17 effector differentiation.…”

“…Whereas a conversion into pTreg cells requires the continuous presence of tolerogenic signals, the imprinted programs promote effector differentiation even under minimally skewing conditions. This work has further revealed a specific expression in such precursors of Homeodomain only protein (Hopx) [ 13 ]. Hopx is a highly evolutionarily conserved small protein that is also present in some differentiated CD4+ effector, memory, and regulatory T cells [ 13 – 15 ].…”

“…This work has further revealed a specific expression in such precursors of Homeodomain only protein (Hopx) [ 13 ]. Hopx is a highly evolutionarily conserved small protein that is also present in some differentiated CD4+ effector, memory, and regulatory T cells [ 13 – 15 ]. However, Hopx has also been recently established as a novel marker of specific developmental potentials in various non-hematopoietic progenitor populations in human and mouse systems [ 15 ].…”

“…However, cDC1 also have powerful tolerogenic functions, whereas cDC2 are considered as more potent in inducing effector T cells [ 10 ]. We now found that in the steady state, antigen presentation by either cDC1 or cDC2 can induce in naïve T cells the specific expression of Hopx, which is indicative of the induction of the “pre-effector” epigenetic and transcriptional programs that pre-commit such T cells toward effector terminal differentiation Therefore, these new findings also help to clarify the dual roles of cDC1 that induce mechanisms of tolerance as well as promote initiation of immune responses even in the absence of specific skewing signals [ 13 ].…”