Transcriptional and epigenetic regulation of T cell hyporesponsiveness

Abstract

Naive CD8 T cells differentiate into effector and memory cytolytic T cells (CTLs) during an acute infection. In contrast, in scenarios of persistent antigen stimulation, such as chronic infections and cancer, antigen-specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8 T cell "exhaustion" or "dysfunction." Another hyporesponsive state, termed "anergy", is observed when T cells are activated in the absence of positive costimulatory signals. Among the many negative regulators induced in hyporesponsive T cells are inhibitory cell-surface receptors, such as PD-1, LAG-3, CTLA-4, and TIM-3; "checkpoint blockade" therapies that involve treatment of patients with cancer with blocking antibodies to those receptors show considerable promise in the clinic because the blocking antibodies can mitigate hyporesponsiveness and promote tumor rejection. In this review, we describe recent advances in our molecular understanding of these hyporesponsive states. We review evidence for the involvement of diverse transcription factors, metabolic programs, and chromatin accessibility changes in hyporesponsive T cells, and we discuss how checkpoint blockade therapies affect the molecular program of CD8 T cell exhaustion.

Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor

“…Over the last several years, we obtained evidence that modulating the formation or stability of the NFAT:AP-1 complex is an attractive way to influence the T cell immune response. In the presence and absence of AP-1, NFAT turns on T cell transcriptional programs of activation versus hyporesponsiveness, respectively (22,25,33); thus, small druglike compounds that stabilize or disrupt the formation of the quaternary NFAT:Fos:Jun:DNA complex without affecting NFAT binding per se could potentially redirect T cell transcription from an "effector" to a "tolerance" program and vice versa.…”

“…Thus, in the early phase of T cell activation, NFAT forms complexes with AP-1 proteins and is involved in the productive immune response, regulating the expression of cytokines, including IL-2, IL-4, IL-5, IL-13, IFN-γ, and GM-CSF (23-25, 27, 30). In contrast, under conditions of prolonged antigen exposure in the absence of costimulation, AP-1 activation dies away (31,32) and NFAT drives a different transcriptional program of T cell anergy and exhaustion, characterized by the expression of inhibitory receptors, such as PD-1, LAG-3, TIM-3, and CTLA-4 (22,33). The genes regulated by NFAT in these two different programs were recently elucidated by our group through genome-wide analyses (22), using T cells expressing a mutant NFAT protein (NFAT-RIT) that does not interact with AP-1 (34), and hence recapitulates the program of anergy/exhaustion induced by NFAT in the absence of costimulation (22).…”

Exhaustion may not be in the human B cell vocabulary, at least not in malaria

“…50 Targeting these receptors with specific antibodies is proving to be successful in awakening exhausted T cells and restoring effector function. Moreover, preliminary studies described above provided evidence the atypical MBCs can be stimulated through their BCR by antigen associated with membranes, the form of the antigen most likely encountered by B cells in vivo.…”

“…For example, exhausted T cells express high levels of the inhibitory receptors PD1, CTLA4, TIM3, LAG3, and TIGIT that leads to a state of hyporesponsiveness. 50 Targeting these receptors with specific antibodies is proving to be successful in awakening exhausted T cells and restoring effector function. [51][52][53] Atypical MBCs also express an array of inhibitory receptors but the overlap with exhausted T cell receptors is small and appears to include only TIM3 and the effect of antibodies specific for these on the B cells' response to antigen has not been determined.…”

“…54 However, T-bet is expressed in effector T cells but not in exhausted T cells. 50 Reversal of exhaustion and induction of effector function with PD1-specific antibody therapy is accompanied by increases in expression of T-bet. 55 Clearly, T-bet may be regulating different genes in atypical MBCs and T cells.…”