Research Article

VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

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Science  17 Jan 2020:
Vol. 367, Issue 6475, eaay0524
DOI: 10.1126/science.aay0524

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A VISTA on naïve T cell fate

T cell quiescence and tolerance restrain the immune system from becoming overactive and attacking healthy tissue. Negative checkpoint regulators normally limit T cell responses to help safeguard against conditions such as autoimmunity. ElTanbouly et al. report that the checkpoint regulator VISTA (V-type immunoglobulin domain-containing suppressor of T cell activation) restricts early stages of T cell activation by shaping the inherent heterogeneity of the naïve CD4+ T cell compartment to one that is more uniformly quiescent and silent (see the Perspective by Brown and Rudensky). Therapeutic targeting of VISTA using an agonistic antibody in mice curbed the development of graft-versus-host disease and promoted the death of naïve T cells abnormally activated by self-antigen. VISTA thus represents a distinctive immunoregulatory molecule that controls naïve T cell function by maintaining quiescence and peripheral tolerance.

Science, this issue p. eaay0524; see also p. 247

Structured Abstract

INTRODUCTION

A central tenet of the clonal selection theory (CST), the current cornerstone of adaptive immunity, states that naïve T cells are selected on the basis of specificity to antigen and that the rest of the repertoire remains agnostic to antigen challenge. However, CST and more recent paradigms have not considered the need for negative regulatory signals to maintain quiescence of the unselected T cells as a pivotal aspect of maintaining clonal selection. Silencing of naïve T cells, or tolerance, also becomes critical upon encounter with self-antigen, whereby self-reactive clones cannot be allowed to develop effector function. These events are known to be interrelated because the loss of quiescence precipitates a loss in tolerance.

RATIONALE

V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is an inhibitory receptor expressed on naïve T lymphocytes, and genetic deletion of VISTA culminates in T cell–mediated autoimmunity. Unlike other negative checkpoint regulators identified to date, VISTA is expressed on naïve T cells, which led us to investigate its function in maintaining naïve T cell quiescence and tolerance.

RESULTS

Using a combination of single-cell RNA sequencing and single-cell ATAC sequencing technologies coupled with in vivo analyses, we investigated the cell-state phenotype of naïve CD4+ (CD44lo CD62Lhi) T cells in mice and found multiple T cell subpopulations exist within a surprisingly heterogeneous naïve T cell compartment. The vast majority of cells display a quiescent phenotype. However, there were subsets expressing less quiescent, memory-like features, a cluster with a high interferon-I (IFN-I) response signature, and a population with higher early T cell receptor (TCR) signaling genes. We show that genetic deletion of VISTA results in a major redistribution of the naïve T cell subsets with the notable reduction of the quiescent subset and the enhanced presence of a memory-like activated T cell subset. In the absence of intrinsic VISTA expression, naïve T cells were more epigenetically and transcriptionally primed toward stronger responses to TCR and cytokine stimulation, providing a rationale for the enhancement of CD44hi CD4+ memory-like T cells observed in the absence of VISTA. As a consequence of reduced quiescence within the naïve T cell compartment, these naïve T cells were less susceptible to tolerance induction. Genetic deletion or antibody blockade of VISTA resulted in significant expansion and reduced tolerance of antigen-specific T cells. These effects were abolished under inflammatory conditions where VISTA expression on antigen-specific T cells was reduced. By contrast, agonistic engagement of VISTA and antigen exposure increased tolerance induction by enhancing the death and deletion of antigen-specific T cells. Tolerogenic death induced by anti-VISTA was demonstrated in a model of acute graft-versus-host disease (GVHD), whereby deletion of donor host reactive T cells resulted in a pronounced therapeutic benefit and long-term survival. The gene signature of VISTA−/− T cells overlapped significantly with T cells from patients with the autoimmune diseases systemic lupus erythematosus and rheumatoid arthritis, suggesting that VISTA may play a broad regulatory role in suppressing T cell self-reactivity.

CONCLUSION

We introduce VISTA as the earliest checkpoint regulator of peripheral T cell tolerance identified to date and describe VISTA as the first of a new class of immunoregulatory molecules whose function is to enforce quiescence in naïve T lymphocytes. In addition, comprehensive epigenetic and transcriptional analyses defined fluorescence-activated sorting-purified CD44lo CD62Lhi naïve CD4+ T cells as heterogeneous. Our current in vivo findings also suggest that regulation of quiescence is inextricably linked to the capacity to maintain T cell self-tolerance. Although a critical player in naïve T cell homeostasis, the restraint enforced by VISTA on naïve T cell responses is lost when antigen stimulation is met under inflammatory conditions.

Loss of VISTA reduces the quiescence phenotype of the naïve T cells at the transcriptional and epigenetic levels, causing enhancement in TCR and cytokine pathways.

(Left) This loss undermines tolerance induction to self-antigen and imparts a more inflammatory phenotype upon activation. KLF2/6, BTG1/2, FOXP1, and SLFN2 are regulators of quiescence. TCF7, BCL2, INFGR1, and SLAMF6 direct memory T cell fate and activity. IFN-γ and CCL5 are effector cytokines. CD69, CD25, and CD40LG are activation and costimulation receptors. (Right) Integration of VISTA with other well-established negative checkpoint regulators of T cell activation. VISTA is constitutively expressed on naïve T cells and plays a critical role in enforcing quiescence. CTLA-4 is expressed on the cell surface briefly after T cell activation and inhibits T cell activation at the priming stage by limiting costimulation. PD-1 is expressed later during priming and inhibits T cells at the effector stage.

Abstract

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

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