Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection

ABSTRACT The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αβ T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αβ T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion/proliferation in organs and blood was higher and more efficient after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection involved the T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire as evidenced by next generation sequencing. The γδ T cell secondary response to MCMV was composed by a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, Long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches. AUTHOR SUMMARY Cytomegalovirus (CMV) is a widespread, latent virus that can cause severe organ disease in immune-compromised patients. Anti-CMV memory immune responses are essential to control viral reactivation and/or reinfection events that commonly take place in solid organ transplantation. The role of γδ T-cell receptor bearing lymphocytes could be crucial in this context where immunosuppressive/ablative treatments cause suboptimal and/or delayed αβ T cell responses. Here we asked whether γδ T cells could compensate for the absence of αβ T cells in the long-term control of mouse CMV infection. Three months post-primary viral challenge in αβ-T cell deficient mice, γδ T cells displayed similar features as cytolytic, CMV-specific αβ CD8 T cells. We showed that previous priming with CMV endowed γδ T cells with an enhanced antiviral potential and that long-term maintenance of γδ-mediated antiviral protection was dependent on γδ central memory T cells (TCM). The γδ T cell response to a secondary CMV challenge was dependent on γδ TCR-signaling and generated a private TCR δ repertoire as observed in human. Our results sustain the adaptive-like properties of these unconventional T cells and reveal the interest of targeting γδ TCM subset in novel antiviral vaccination approaches