The direct comparison of inhibitory receptor profiles across multiple Ag-specific CD4 T cells circulating in peripheral blood provides compelling and novel evidence that the majority of Mtb-specific CD4 T cells do not upregulate co-expression of multiple inhibitory receptors, regardless of HIV infection status, and that Ag-specific CD4 T cells circulating in HIV-infected individuals display markedly different phenotypic profiles, depending on the Ag specificity. Here, CD4 is linked to HIV infectious disease.