Increased Memory Differentiation Is Associated with Decreased Polyfunctionality for HIV but Not for Cytomegalovirus-Specific CD8+ T Cells

Abstract

The generation of polyfunctional CD8+ T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8+ T cells within different memory subpopulations in 20 ART-naïve HIV-1 infected individuals at approximately 34 weeks post infection. These profiles were compared with CMV-specific CD8+ T cell responses in HIV-uninfected controls and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8+ T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO+CD27+) exhibited a higher proportion of cells positive for three or four functions (p<0.001), and a lower proportion of mono-functional cells (p<0.001) compared to terminally-differentiated (CD45RO−CD27−) HIV-specific CD8+ T cells. The majority of terminally-differentiated HIV-specific CD8+ T cells were mono-functional (median 69% [IQR: 57–83]), producing predominantly CD107a or MIP1β. Moreover, proportions of HIV-specific mono-functional CD8+ T cells positively associated with proportions of terminally-differentiated HIV-specific CD8+ T cells (p=0.019, r=0.54). In contrast, CMV-specific CD8+ T cell polyfunctional capacities were similar across all memory subpopulations, with terminally- and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8+ T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses.

Differences in antigen‐specific CD4+ responses to opportunistic infections in HIV infection

“…Our data indicate pathogen-related variance in expression of CD45RA and CCR7 of some subsets analogous to work on CD8+ cells 28,29 and CD4+ cells 30. CD4+ cells secreting IL-2 with or without other cytokines were principally derived from the T CM subset irrespective of pathogen specificity.…”

Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

“…Few studies have examined polyfunctional CD4 or CD8 T cell responses in infants, which were detected infrequently in congenital HIV infection [65, 66], but commonly and with heterogeneous phenotype and functional profiles following Bacillus Calmette-Guérin vaccination [35, 67]. Similar to these studies, our work shows that infants with congenital CMV infection are relatively incapable of generating polyfunctional T cell responses, but when present, expression patterns were similar to adults and included CD107 and MIP1β with or without IFNγ [64]. …”

“…Among adults, CMV pp65-specific CD8 T cells are skewed toward robust cytotoxic and chemotaxis functions, a profile consistent with effector responses and the capacity to recruit cells to local sites of viral replication [63, 64]. In particular, Kim et al [63] showed that late memory (CD27−CD45RA+) CMV pp65-specific CD8 T cells in healthy adults produce little IL2 but abundant MIP1β.…”

Restoration of CD4+ Responses to Copathogens in HIV-Infected Individuals on Antiretroviral Therapy Is Dependent on T Cell Memory Phenotype

“…Figure 4A shows a representative contour plot of distinct memory subsets in the CD4 compartment pre-ART in one HIV-infected individual. Based on the expression of CD45RO and CD27, we were able to discriminate four different memory subpopulations (32), namely: Naïve (CD45RO-CD27+), Early Differentiated (ED: CD45RO+CD27+, encompassing central and transitional memory subsets), Late Differentiated (LD: CD45RO+CD27−, encompassing effector memory cells) and Terminally Differentiated (TD: CD45RO-CD27−, or effector cells). In HIV-infected subjects, although Mtb- and CMV-specific CD4+ T cells were represented in both ED and LD subsets, they comprised significantly distinct profiles (Figure 4B, left panel).…”