Examining the immune-biology of activated gamma delta T-cells in healthy and simian HIV-infected macaques.

摘要

The major subset of circulating human gamma delta (gammadelta) T-cells recognize a foreign non-peptide phosphoantigen (HMBPP) produced by a wide variety of bacteria and parasites as well as related self antigens overproduced by stressed or transformed cells. Accumulating evidence suggests that these gammadelta T-cells play a role in antimicrobial, antiviral and anticancer immunity. Numerous in vitro studies have shown that activated gammadelta T-cells can directly kill various infected/malignant-cells. Much enthusiasm has been raised about targeting human gammadelta T-cells as potential immunotherapy for the treatment of a wide variety of infectious diseases and neoplasms. However, many aspects of the immune-biology of these cells remain to be clearly defined and the functions of these cells appear to be compromised during HIV infection.;We have employed macaques as a non-human primate model to establish a drug regimen comprised of the phosphoantigen HMBPP plus IL-2 to target the activation/expansion of gammadelta T-cells. We found that HMBPP-activated gammadelta T-cells are capable of (1) massively proliferating in the circulation (2) accumulating/migrating to various mucosal surfaces, particularly the lung (3) responding to further antigenic stimulation by potent production of proinflammatory/antimicrobial cytokines (e.g. IFNgamma) as well as cytotoxic proteins (e.g. perforin) and (4) potentially impacting conventional alphabeta T cell responses.;Next, as initial efforts to explore gammadelta T-cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether our well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune-suppression to massively expand polyfunctional gammadelta T-cells, and whether such activation/expansion could impact AIDS pathogenesis in SHIV-infected macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of gammadelta T-cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly could confer immunological benefits by boosting anti-viral and anti-bacterial responses. Thus, HMBPP/gammadelta T-cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV-infected individuals.