T regulatory cells are critical for the maintenance, anamnestic expansion and protection elicited by vaccine‐induced CD8 T cells

Abstract

T regulatory (Treg) cells are critical for preventing autoimmunity and suppressing immune responses during cancer and chronic infection. However, the role of Treg cells in the generation of vaccine-induced immune memory remains ill-defined. Using the mouse model of lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate that transient absence of Treg cells during effector to memory CD8 T-cell transition results in a permanent impairment in the maintenance, function and recall capacity of CD8 T cells. Memory CD8 T cells in mice that were transiently depleted of Treg cells exhibited defective up-regulation of memory markers with a significant decrease in polyfunctionality. However, Treg-depleted mice showed no significant change in CD4 T-cell responses, and antibody levels relative to control. Altogether, this study evaluates the role of Treg cells in the formation of immune memory and demonstrates an important role for Treg cells in promoting memory CD8 T-cell differentiation and vaccine-induced immune protection against intracellular pathogens.

A universal anti‐cancer vaccine: Chimeric invariant chain potentiates the inhibition of melanoma progression and the improvement of survival

“…Tregs play a major role in maintenance of self-tolerance in healthy hosts, and may hamper an effective antitumor immune response. 49,50 Importantly, we found a non-significant trend of elevated frequencies of these immunosuppressive cells in control groups compared to construct immunized groups. Another crucial immunosuppressive cell population is represented by MDSCs that inhibit antitumor T-cell responses by multiple mechanisms and can be considered as one of the most important components of tumor-induced immunosuppression in melanoma.…”

Interrogating Adaptive Immunity Using LCMV

“…PD-1-based immunotherapy for the treatment of chronic infection was first shown in the chronic LCMV Cl-13 model (Barber et al, 2006), and was then shown to also be effective in the SIV model in macaques (Velu et al, 2009). Many studies on immune regulation have utilized the LCMV system (Bhattacharyya et al, 2017b;Bhattacharyya & Penaloza-MacMaster, 2017, 2018Im et al, 2016;Kamphorst et al, 2017;Penaloza-MacMaster et al, 2011;Penaloza-MacMaster, Kamphorst et al, 2014;Penaloza-MacMaster, Masopust, & Ahmed, 2009;Penaloza-MacMaster, Provine, Blass, & Barouch, 2015;Penaloza-MacMaster, Teigler et al, 2014;Vezys et al, 2011;Wang et al, 2019;West et al, 2013;West et al, 2011).…”

CD8 T‐cell regulation by T regulatory cells and the programmed cell death protein 1 pathway

“…Following LCMV challenge (acutely controlled or chronic), PD‐1 levels are transiently increased on activated CD8 T cells at the peak of the effector CD8 T‐cell response . The peak of the effector CD8 T‐cell response coincides with a time when Treg cell responses transiently collapse . If the LCMV infection is controlled, PD‐1 and Treg cells return to normal pre‐challenge levels, but if the infection persists, PD‐1 is maintained at high levels and Treg cells rebound to very high numbers, heralding the exhaustion of CD8 T cells …”

“…54 The peak of the effector CD8 T-cell response coincides with a time when Treg cell responses transiently collapse. 45,88 If the LCMV infection is controlled, PD-1 and Treg cells return to normal pre-challenge levels, but if the infection persists, PD-1 is maintained at high levels and Treg cells rebound to very high numbers, heralding the exhaustion of CD8 T cells. 45,54,79,88 Concluding remarks and future directions Treg cells play context-dependent roles in the immune response: they suppress exhausted CD8 T-cell responses during antigen persistence, but promote memory CD8 Tcell responses during acute antigen clearance.…”

“…45,88 If the LCMV infection is controlled, PD-1 and Treg cells return to normal pre-challenge levels, but if the infection persists, PD-1 is maintained at high levels and Treg cells rebound to very high numbers, heralding the exhaustion of CD8 T cells. 45,54,79,88 Concluding remarks and future directions Treg cells play context-dependent roles in the immune response: they suppress exhausted CD8 T-cell responses during antigen persistence, but promote memory CD8 Tcell responses during acute antigen clearance. PD-1 also exerts inhibitory effects on exhausted CD8 T cells during chronic infections and cancers, but this pathway does not seem to play a critical role in modulating memory CD8 T cells during acutely controlled antigen challenges.…”