Abstract
Cytomegalovirus (CMV) infection is associated with immune-suppression in immune-compromised hosts and old adults. We previously showed that ex vivo CMV restimulation of peripheral blood mononuclear cells (PBMC) of CMV-seropositive volunteers expanded CD4+CD27-CD28- regulatory T cells (Tregs). Here we evaluate the phenotype and function of circulating CD4+CD27-CD28- T cells of CMV-seropositive adults. Compared with CMV-seronegative, CMV-seropositive adults had 10-fold higher CD4+CD27-CD28-% T cells in PBMC. Circulating CD4+CD27-CD28- T cells from both CMV-seropositive and seronegative donors expressed higher levels of TGFβ, granzyme B, CD39, CD147 and IL-35, and lower levels of CD127, compared with their parent circulating CD4+ T cells. However, only CMV-seropositive circulating CD4+CD27-CD28- had increased FOXP3 expression. CD4+CD27-CD28- sorted from the PBMC of CMV-seropositive donors expanded ex vivo in the presence of rhIL2 and inhibited ex vivo proliferation of autologous PBMC restimulated with CMV, varicella-zoster virus or C. albicans antigens. CD4+CD27-CD28- sorted from CMV-seronegative PBMC did not expand in the presence of rhIL2 and did not inhibit autologous PBMC proliferation. CD3+CD27-CD28- circulating T cells (≥80% CD8+) from CMV-seropositive HIV-infected donors also inhibited ex vivo proliferation of autologous PBMC restimulated with CMV or HIV. These data indicate that CMV-seropositive individuals have circulating Tregs that inhibit cell-mediated immune responses to CMV and other antigens and may be contribute to an immune-suppressive effect of CMV infection. Moreover, the phenotypic similarity between circulating CD4+CD27-CD28- Tregs with differentiated effector T cells suggests that the two T-cell subsets might evolve in parallel or in sequence from the same progenitor cells in response to CMV stimulation during reactivations.
Highlights
Cytomegalovirus (CMV)-infected individuals with cell-mediated immune disorders, such as transplant recipients and human immunodeficiency virus (HIV)-infected individuals, or at the extremes of age without any age-independent immune disorders have higher morbidity and mortality than uninfected individuals [1,2,3,4,5,6,7]
We propose that the regulatory CD4+CD27-CD28- and CD8+CD27-CD28- T cells of CMV-seropositive individuals contribute to the immune suppression associated with CMV infection
We showed that in vitro stimulation of peripheral blood mononuclear cells (PBMC) from CMV-seropositive donors increased the proportion of CD4 +CD27-CD28- T cells, in HIV co-infected subjects [15]
Summary
Cytomegalovirus (CMV)-infected individuals with cell-mediated immune disorders, such as transplant recipients and human immunodeficiency virus (HIV)-infected individuals, or at the extremes of age without any age-independent immune disorders have higher morbidity and mortality than uninfected individuals [1,2,3,4,5,6,7]. CMV replicates in many cells of the immune system including monocytes, macrophages and dendritic cells and subsequently establishes latency in CD34 + myeloid progenitors. Both during active and latent infection, the virus employs immune evasion mechanisms that allow it to survive in the host by suppressing host immune responses [12]. The hypothesis that regulatory T cells (Treg) expanded in response to a specific pathogen may be cross-reactive and impair immune defences against other pathogens is supported by several mouse studies that showed that Treg expanded by chronic infection with Friend retroviruses suppress immunity to murine CMV [13, 14]
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