HIV-1-specific IFN-γ/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells

Abstract

Functional and phenotypic characterization of virus-specific CD8 T cells against cytomegalovirus, Epstein-Barr virus, influenza (flu), and HIV-1 were performed on the basis of the ability of CD8 T cells to secrete IFN-γ and IL-2, to proliferate, and to express CD45RA and CCR7. Two functional distinct populations of CD8 T cells were identified: ( i ) dual IFN-γ/IL-2-secreting cells and ( ii ) single IFN-γ-secreting cells. Virus-specific IFN-γ/IL-2-secreting CD8 T cells were CD45RA - CCR7 - , whereas single IFN-γ CD8 T cells were either CD45RA - CCR7 - or CD45RA + CCR7 - . The proportion of virus-specific IFN-γ/IL-2-secreting CD8 T cells correlated with that of proliferating CD8 T cells, and the loss of HIV-1-specific IL-2-secreting CD8 T cells was associated with that of HIV-1-specific CD8 T cell proliferation. Substantial proliferation of virus-specific CD8 T cells (including HIV-1-specific CD8 T cells) was also observed in CD4 T cell-depleted populations or after stimulation with MHC class I tetramer-peptide complexes. IL-2 was the factor responsible for the CD4-independent CD8 T cell proliferation. These results indicate that IFN-γ/IL-2-secreting CD8 T cells may promote antigen-specific proliferation of CD8 T cells even in the absence of helper CD4 T cells.

Polyfunctional HCV‐specific T‐cell responses are associated with effective control of HCV replication

“…These results show that HCV-specific T cells in HCV monoinfection have a polyfunctional profile similar to that of virusspecific CD4 1 and CD8 1 T cells found in normally controlled infections with low or undetectable persistent viral load such as CMV, EBV, HSV, influenza and HIV-1-infected subjects with nonprogressive disease [22,25,28]. In contrast, HCV-specific T-cell responses in HIV/HCV co-infected individuals and liver transplant recipients have the ''only effector'' profile and resemble those detected in uncontrolled viral infections such as untreated viremic HIV-1 infection [22,25]. The reduction in IL-2-producing CD4 1 and CD8 1 T cells can directly explain the impaired capacity of these cells to proliferate [25].…”

“…Recent studies have indeed shown that the proliferation capacity of virus-specific CD4 and CD8 T cells is dependent upon the presence of IL-2-producing cells and that the presence of virus-specific proliferating cells is associated with control of virus replication [22,24,25]. Both CD4 1 ( Fig.…”

“…In addition, it has also been shown that ''only effector'' and polyfunctional T-cell responses were generally associated with higher and lower levels of viral load in CMV and HIV-1 infection, respectively [22,25]. Therefore, we investigated whether higher levels of HCV viral load were present in HIV/HCV co-infected patients and liver transplant recipients compared with HCV mono-infected patients.…”

“…It has been shown that polyfunctional T-cell responses were associated with more effective control of virus replication and lower viral load in chronic virus infections such as CMV, EBV, HCV, HIV-1 and HSV infections [22,25] whereas ''only effector'' T-cell responses were associated with higher viral load. As mono/ polyfunctionality of T-cell responses are predominantly defined by the ability of CD4 and CD8 T cells to produce IL-2 and to proliferate, we analyzed these parameters in chronic HCV monoinfection, HIV/HCV co-infection and in liver transplant recipients.…”

“…In particular, it has been shown that immune responses associated with effective virus clearance or control (low to undetectable viral load) were predominantly composed of polyfunctional CD4 1 and CD8 1 T cells. Polyfunctionality has been defined by the ability of both CD4 1 and CD8 1 T cells to produce cytokines such as IL-2 and IFN-g and to proliferate [22][23][24][25]. Other cytokines such as MIP-1b and TNF-a and functions such as degranulation activity and perforin expression are instrumental to better characterize the functional profile of T cells but do not discriminate between polyfunctional and ''only effector'' T-cell responses.…”