Background:  Several studies performed in mice and humans have demonstrated wide heterogeneity of memory CD4 T cells. Multiple phenotypes and a broad spectrum of functions have been observed in different viral infections.

Methods:  We have addressed this issue by analyzing different models of memory CD4 T-cell responses in 18 HIV-1-infected subjects with chronic progressive infection, 7 HIV-1-infected subjects with non-progressive infection, and 50 HIV-negative subjects. We used  tetanus toxoid (TT) as a model of memory T-cell response where the antigen is cleared;  the Cytomegalovirus (CMV) chronic infection as a model of repetitive antogen exposure and low antigen load; and HIV-1 infection as a model of antigen persistence and high antigen load. Immune responses were characterized using multi-parametric flow cytometry.

Results:  The TT-specific CD4 T cells were mostly composed of single IL-2-secreting cells, the 3 distinct cytokine-secreting CD4 T-cell populations (single IL-2, IL-2-IFN-g and single IFN-g) were well represented within CMV-specific T cells, and single IFN-g-secreting cells dominated the HIV-1-specific T-cell response. We then determined the effects of changes in antigen exposure and antigen load within the 3 models of immune response. After re-immunization, we observed a substantial increased (about 5-fold) in the percentage of TT-specific single IL-2- secreting CD4 T cells with a peak at day 11 and, more interestingly, we observed the appearance of IL-2-IFN-g and single IFN-g-secreting cells. The newly generated cell populations were CD45RA^-CCR7^- while the single IL-2-secreting CD4 T cells that served as precursors were CD45RA^-CCR7⁺. The large majority (about 90%) of CMV-specific CD4 T cells were single IFN-g-secreting cells, about 10% were IL-2-IFN-g-secreting cells, and single IL-2-secreting cells were almost absent during primary CMV infection. The majority of CMV-specific cells were CD45RA^-CCR7^- while the CD45RA⁺CCR7^- cell population, present in chronic infection, was absent. The 3 distinct cytokine secreting CD4 T-cell populations were equally represented in the HIV-1-infected subjects with non-progressive disease and low antigen load or following virus suppression by antiviral therapy in subjects with progressive disease.

Conclusions:  Antigen persistence and antigen load appear to influence substantially the composition of functional and phenotypically distinct CD4 cell populations in different models of immune response.

Keywords: Virus-specific CD4 T Cells; Antigen persistence/load; heterogeneity