Tc1 effector diversity shows dissociated expression of granzyme B and interferon-γ in HIV infection

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Abstract
Objective: To examine antigen specific cytotoxic effector T cell diversity in HIV infected individuals. Design: We used a panel of previously defined HLA class I-restricted HIV peptides to stimulate CD8 cells in freshly isolated peripheral blood mononuclear cells of HIV infected patients, to determine cognate killing via the perforin–granzyme pathway and inflammation induced by secretion of interferon (IFN)-γ. Methods: ELISPOT assays were used to measure the secretion of granzyme B (GzB) and IFN-γ at single cell resolution. Results: In all nine patients only approximately 20% of the peptides triggered a canonical Tc1 response with simultaneous release of GzB and IFN-γ. The majority of these peptides (approximately 80%) that elicited recall responses fell into the ‘single positive’ category with induction of either GzB or IFN-γ alone. The GzB positive cells did not produce interleukin (IL)-4 or IL-5. Conclusion: The GzB positive but IFN-γ negative CD8 cells are programmed to induce apoptosis mediated killing without inflammation while the GzB negative and IFN-γ positive CD8 cells could mediate inflammation without killing. This Tc1 CD8 effector cell diversity and the understanding of these differentiation mechanisms may enable the precise implementation and fine-tuning of fundamentally different defense strategies against HIV and other infections.