Role of host lymphopenia in the immune reconstitution disease triggered by CD4 T cell transfer into mycobacterial infected T cell deficient mice (40.20)

Abstract

Abstract Approximately 10-30% of HIV patients develop a paradoxical inflammatory disease shortly after beginning anti-retroviral therapy (ART), termed Immune Reconstitution Inflammatory Syndrome (IRIS), that is emerging as a major problem in the clinical management of the HIV pandemic. Patients with the lowest CD4 counts, the most rapid drop in viral loads after ART and an AIDS defining illness, such as mycobacterial infection, are at highest risk. This indicates that T cell reconstitution itself may be pathogenic rather than beneficial when CD4 T cells suddenly repopulate a lymphopenic host harboring an opportunistic infection. Here we demonstrate that a rapidly fatal wasting occurs in mice when CD4 T cells are transferred into Mycobacterium avium infected TCRαKO animals. This reconstitution disease was dependent on IFNγ and TNFα but not IL-4 or IL-17A. Non-specific T cells induced no disease, but transfer of T cells specific for bacterial or endogenous antigens was rapidly lethal. Importantly, M. avium infected TCRαKO and ovalbumin-specific TCR Tg mice were susceptible hosts, whereas M. avium-specific TCR Tg mice were resistant to reconstitution disease. These data demonstrate that during M. avium infection of lymphopenic hosts the lack of bacteria-specific T cells, rather than the lymphopenic environment per se, predisposes the host to develop reconstitution disease when repopulating CD4 T cells encounter Ag. This work was supported by the NIAID intramural research program.