Regulatory T cells and T‐cell‐derived IL‐10 interfere with effective anti‐cytomegalovirus immune response

Abstract

Cytomegalovirus (CMV) establishes lifelong chronic infection in its host with mostly asymptomatic or only mild disease, but under immunosuppressive conditions the virus can reactivate and infection can cause life-threatening disease. CMV has evolved several mechanisms to escape from host's immunity, allowing persistence of the virus. Until now, it remains elusive whether regulatory T cells (Tregs) have an impact on insufficient host immune response against the virus in this context. In the present study, we provide evidence that CD4(+)Foxp3(+) naturally occurring Tregs (nTregs) as well as CD4(+)Foxp3(-)IL-10(+)-induced Tregs (iTregs) interfere with an effective anti-mouse CMV (mCMV) immune response. Depletion of Foxp3(+) Tregs by using DEREG mice resulted in enhanced T-cell activation as measured by the expression of CD62L, granzyme B and interferon (IFN)-γ and was associated with reduced viral titers in salivary glands, the organ where mCMV mainly persists. Moreover, we identified CD4(+)Foxp3(-) T cells to produce elevated levels of the immunosuppressive cytokine IL-10 at early time points during mCMV infection. Analysis of T-cell activation and viral replication in mCMV-infected IL-10(flox/flox) × CD4-cre mice and IL-10(flox/flox) × FIC mice revealed that T-cell-specific inactivation of IL-10, but not Foxp3(+) Treg-specific IL-10 ablation alone, resulted in elevated IFN-γ production by T cells associated with a significant decrease in viral loads in salivary glands. Thus, our data illustrate a crucial role for CD4(+)Foxp3(+) nTregs as well as IL-10-producing CD4(+)Foxp3(-) iTregs in the regulation of appropriate T-cell responses and viral clearance during mCMV infection.

Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence

“…HCMV-encoded latency associated antigens induce CD4 + /IL-10 + responses in healthy donors [30]. MCMV-specific IL-10 production by CD4 + T cells has also been described [17,31,32], and CD4 + cell-derived IL-10 suppresses control of virus replication and leukocyte accumulation during acute MCMV infection [33]. A substantial proportion of CD4 + T cells express IL-10 upon polyclonal stimulation in salivary glands during MCMV persistence [18].…”

Primate neural retina upregulates IL-6 and IL-10 in response to a herpes simplex vector suggesting the presence of a pro-/anti-inflammatory axis

“…In the mouse retina, increased IL-10 expression was detected in photoreceptor and Muller cells and is thought to protect the neuroretinal cells from the toxic effects of pro-inflammatory cytokines during EAU (Lee et al, 2011). IL-10 production is stimulated in murine HSV-1 and mCMV retinitis and is believed to play a role in down regulation of pro-inflammatory cytokines and viral clearance (Blalock et al, 2013; Jost et al, 2014; Saitoh-Ishibashi et al, 2003). Since hrR3 induces uveitis in NHP but not in mice, it is not clear that data in mice are translatable to NHPs.…”

Cytokine Profiles in Aqueous Humor and Plasma of HIV-infected Individuals with Ocular Syphilis or Cytomegalovirus Retinitis

“…A role for the Treg-derived IL-10 cytokine should also be considered, as we and others 12 found higher levels of this immunoregulatory cytokine in the plasma of individuals with CMVr, which has been shown to interfere with effective anti-CMV immune responses. 26 Although individuals with CMVr have a more advanced HIV infection than individuals with ocular syphilis, and plasma cytokine concentrations seem to be determined mostly by the stage of HIV disease and in a lesser extent by the type of ocular infection, differences found in the AqH compartment reflect a local response with unique signatures for each OI. Previous studies 11,12 and ours, have found a strong ocular inflammatory response associated with CMVr, suggesting an important role of monocytes producing innate mediators for Th1-driven anti-viral responses in the context of a severely depleted CD4+ T cell pool.…”