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.