Skewing of the CD4+ T cell pool towards mono-functional antigen-specific responses in patients with immune reconstitution inflammatory syndrome in The Gambia

Background. A common complication of starting anti-retroviral therapy (ART) for HIV is the development of Immune Reconstitution Inflammatory Syndrome (IRIS) in approximately 25% of patients. Despite similarities with paradoxical reactions to tuberculosis and reversal reactions in leprosy, the exact mechanisms, and therefore potential determinants, of IRIS are still unknown. Methods. In this longitudinal cohort study, we analysed 20 patients who developed IRIS following initiation of ART and 16 patients who did not; matched for ART time-point. PBMC were stimulated overnight with a positive control antigen and two TB-specific antigens (PPD and Esat-6/CFP10) followed by polychromatic flow cytometry for analysis of cytokine production from CD4+ and CD8+ T cells. Results. Responses to PPD were significantly higher in IRIS patients compared to controls during the IRIS time-point but CD4+ and CD8+ T cell responses to the positive control stimulation were significantly lower in IRIS patients at all time-points. Furthermore, whilst control patients had rejuvenated polyfunctional (CD4+IFNgamma+IL2+TNFalpha+) T cell responses by 3-months post-ART, IRIS patients were strikingly mono-functional (generally IFN-gamma alone), even up to 6 months of ART in response to all stimulations. Conclusions. Our findings suggest that the peripheral T responses to the underlying pathogen are exaggerated in IRIS patients but the overall quality of the peripheral T cell pool is significantly reduced compared to non-IRIS patients. Furthermore, these effects are apparent at least up to 3 months post-cessation of IRIS.