Differential expression of CXCR3 and CCR6 on CD4(+) T-lymphocytes with distinct memory phenotypes characterizes tuberculosis-associated immune reconstitution inflammatory syndrome

Immune reconstitution inflammatory syndrome (IRIS) occurs in up to 40% of individuals co-infected with pulmonary tuberculosis (PTB) and HIV, primarily upon antiretroviral therapy (ART) initiation. Phenotypic changes in T-cells during TB-IRIS and their relationship with systemic inflammation are not fully understood. In this prospective cohort study, we followed 48 HIV-positive patients with PTB from South India before and after ART initiation, examining T-lymphocyte subsets and inflammatory biomarkers in peripheral blood. Quantification of naïve (CD27(+)CD45RO(−)) as well as effector memory CD4(+) T cells (CD27(−)CD45RO(+)) at weeks 2–6 after ART initiation could distinguish TB-IRIS from non-IRIS individuals. Additional analyses revealed that ART reconstituted different quantities of CD4(+) T lymphocyte subsets with preferential expansion of CXCR3(+) CCR6(−) cells in TB-IRIS patients. Moreover, there was an expansion and functional restoration of central memory (CD27(+)CD45RO(+)) CXCR3(+)CCR6(−) CD4(+) lymphocytes and corresponding cytokines, with reduction in CXCR3(−)CCR6(+) cells after ART initiation only in those who developed TB-IRIS. Together, these observations trace a detailed picture of CD4(+) T cell subsets tightly associated with IRIS, which may serve as targets for prophylactic and/or therapeutic interventions in the future.