T Regulatory Cells Contribute to the Attenuated Primary CD8+ and CD4+ T Cell Responses to Herpes Simplex Virus Type 2 in Neonatal Mice

Abstract

The first weeks of life are characterized by immune tolerance and increased susceptibility to intracellular pathogens. The neonatal adaptive response to HSV is attenuated compared with adult control models in humans and mice. T Regulatory cells (Tregs) control autoimmunity and excessive immune responses to infection. We therefore compared Treg responses in the draining lymph nodes (LN) of HSV-infected neonatal and adult C57BL/6 mice with the effect of Treg depletion/inactivation by anti-CD25 (PC61) treatment before infection on Ag-specific T cell effector responses at this site. There was a small, but significant increase in the frequency of CD4+Foxp3+ Tregs at day 3 postinfection (p.i.) in the LN of neonatal and adult mice, compared with age-matched mock-infected controls. Depletion of Tregs before HSV infection significantly enhanced HSV-specific CD8+ T cell cytotoxicity in vivo, cell number, activation, and granzyme B expression 4 days p.i. only in neonatal mice, and significantly enhanced CD8+ and CD4+ T cell IFN-γ responses in both infected adults and neonates. Treg depletion also reduced the titer of infectious virus in the draining LN and nervous system of infected neonates on days 2 and 3 p.i. Treg suppression of the neonatal CTL response p.i. with HSV was associated with increased expression of TGF-β in the draining LN at day 4 p.i. compared with uninfected neonates, but IL-10 was increased in infected adults alone. These experiments support the notion that the newborn primary T cell effector responses to HSV are suppressed by Tregs.

Pathological Role of Regulatory T Cells in the Initiation and Maintenance of Eczema Herpeticum Lesions

“…However, we could not totally exclude the possibility that an increase in the frequencies of Tregs is a secondary event that requires and follows the reactivation of HSV or clinical exacerbation. Consistent with this possibility, a number of microbial pathogens, including HSV, were shown to increase the frequency of Tregs in infected tissues or lymphoid organs of adult mice and humans (5). These findings suggested that the increase in the frequencies of Tregs that we observed at the onset of EH might be a consequence, not a cause, of viral reactivation or a clinical exacerbation.…”

“…Because CD4 + regulatory T cells (Tregs) are known to suppress such excessive adaptive immune responses to HSV (5), thereby limiting immunopathology, it has been tempting to speculate that an imbalance in the proportion of effector T cells to Tregs may contribute to the development of EH. A number of previous studies (6,7) yielded conflicting findings on the frequency of circulating Tregs in patients with AD.…”

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

“…However, T regs are mostly immunosuppressive, as they have been shown to suppress effector T cell functions and autoimmunity by mechanisms involving cellcell contact and subsequent delivery of inhibitory signals (11,12). A link between T regs and granzyme B is evident in that depletion of T regs enhances granzyme B expression in virally infected mice (11).…”

“…At least two types of T regs have been shown to use granzyme-mediated killing: natural T regs can use granzyme A to induce cell apoptosis, and inducible T regs (Tr1/Th3 cells) can use granzyme B (10). However, T regs are mostly immunosuppressive, as they have been shown to suppress effector T cell functions and autoimmunity by mechanisms involving cellcell contact and subsequent delivery of inhibitory signals (11,12). A link between T regs and granzyme B is evident in that depletion of T regs enhances granzyme B expression in virally infected mice (11).…”

Regulatory T-cell: Regulator of Host Defense in Infection

“…These regulatory cells may also protect the patients from pathologic disorders and viral-induced inflammation in chronic HCV infection(Claassen, (Rouse, Sarangi, & Suvas, 2006). This was supported by the fact that, depletion of Tregs from cases with HSV infection significantly enhanced the protective immunity (Fernandez et al, 2008). In HIV infection the level of regulatory T-cells in lymph nodes and blood may be significantly high.…”