Complement controls antiviral CD8+T cell memory development and function

Abstract

Abstract Control of infectious disease is predicated on the combined efforts of both innate and adaptive immune defenses including the generation of pathogen-specific CD8+effector T cells (CD8+TE). Upon resolution of inflammation and pathogen clearance, the CD8+TE population contracts and the preferential survivors mature into CD8+TM, which provide further protection against recurrent infection. In this context, the precise properties of CD8+TM populations emerge as a consequence of the unique conditions during initial T cell priming and thus make the generation of T cell memory contingent upon a variety of co-stimulatory and -inhibitory interactions. Here, we demonstrate a non-redundant role for complement, an innate immune defense pathway, in the development of CD8+T cell memory generated in response to an acute lymphocytic choriomeningitis virus (LCMV) infection. Mice deficient for the complement component 3 (C3) mount a relatively normal LCMV-specific CD8+T cell response, yet the subsequent development of CD8+T cell memory is compromised by impaired phenotypic, metabolic and functional CD8+TM maturation. Interestingly, the contraction phase is also impaired which results in an increased abundance of CD8+TM. Despite this observation, C3-deficient CD8+TM exhibit a decreased capacity to undergo in vivo secondary expansion when adoptively transferred into naïve hosts for rechallenge. We propose that C3, but no other individual complement component evaluated (C3aR, C5aR, and DAF/CD55), exerts a unique co-stimulatory function that generates a balanced formation of CD8+T cell memory and recall responses.