Regulatory T Cells Shape the Resident Memory T Cell Response to Virus Infection in the Tissues

Abstract

Regulatory T cells (Tregs) are well known for their role in dampening the immune responses to self-antigens and thereby limiting autoimmunity. However, they must also permit immune responses to occur against foreign infectious agents. Using a mouse model of West Nile virus (WNV) infection, we examined the role of Tregs in the generation of effector and memory T cell responses in the secondary lymphoid organs (SLO) as well as the infected tissues. We found that Treg numbers and activation increase in both the SLO and CNS after infection. Using the Foxp3DTR knock-in mice, we found that Treg-deficient mice had increased antigen-driven production of IFN-γ from both CD4+ and CD8+ T cells in both the spleen and CNS during the effector phase. In mice lacking Tregs, there were greater numbers of short-lived effector CD8+ T cells in the spleen during the peak of the immune response, but the memory CD8+ T cell response was impaired. Specifically, we demonstrate that Treg-dependent production of TGF-β results in increased expression of CD103 on CD8+ T cells, thereby allowing for a large pool of resident memory T cells to be maintained in the brain after infection.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…110 TGF-β signaling likely promotes the induction of CD103 + brain T RM cells as depletion of Foxp3 + regulatory T cells (Tregs) and Treg-derived TGF-β impairs the formation of brain T RM population. 127 Further, similar as kidney T RM cells, TGF-β promotes the trans-endothelial migration of CD8 + effector T cells into the brain. 109 Locally produced survival cytokines IL-7 and/or IL-15 may promote brain T RM homeostasis as a sizable population of brain T RM s contains phosphorylated STAT5 and undergoes homeostasis proliferation in vivo.…”

Quiescence of Memory CD8+ T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4

“…However, effector and memory T cell clones primed in the absence of Treg cells are typically of low avidity (Pace et al, 2012). Absence of Treg cells during primary T cell responses is also associated with a dysregulation of the chemokine milieu (Lund et al, 2008;Pace et al, 2012), altered T cell localization (Graham et al, 2014), and compromised pathogen clearance (Lund et al, 2008). Prolonged instructional cues from antigen or cytokines such as interleukin-2 (IL-2) and IL-12, which may occur due to loss of Treg cells during priming, are associated with terminal effector differentiation and impaired programming of memory potential (Joshi et al, 2007;Kalia et al, 2010a;Kalia et al, 2010b;Sarkar et al, 2008).…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…[103][104][105] Thus, although there is no direct correlation between the CD4 1 T lymphocyte response and the infectious virus titer in MCMVinfected newborn mouse brains, 74 CD4 1 T lymphocytes may contribute to viral control in the CNS by providing crucial accessory functions for virus-specific CD8 1 T cells, as shown for other infections (Figure 3b). 106,107 The accumulation of virus-specific B-lineage cells within the CNS is a hallmark of many neurotropic viral infections. [108][109][110] A model of intracranial MCMV infection of mice demonstrated Bcell recruitment into the CNS with a steady increase throughout the time-course of infection.…”