Interleukin-27 promotes CD8 ⁺ T cell reconstitution following antibody-mediated lymphoablation

Abstract

Antibody-mediated lymphoablation is used in solid organ and stem cell transplantation and autoimmunity. Using murine anti-thymocyte globulin (mATG) in a mouse model of heart transplantation, we previously reported that the homeostatic recovery of CD8 ⁺ T cells requires help from depletion-resistant memory CD4 ⁺ T cells delivered through CD40-expressing B cells. This study investigated the mechanisms by which B cells mediate CD8 ⁺ T cell proliferation in lymphopenic hosts. While CD8 ⁺ T cell recovery required MHC class I expression in the host, the reconstitution occurred independently of MHC class I, MHC class II, or CD80/CD86 expression on B cells. mATG lymphoablation upregulated the B cell expression of several cytokine genes, including IL-15 and IL-27, in a CD4-dependent manner. Neither treatment with anti-CD122 mAb nor the use of IL-15Rα ^–/– recipients altered CD8 ⁺ T cell recovery after mATG treatment, indicating that IL-15 may be dispensable for T cell proliferation in our model. Instead, IL-27 neutralization or the use of IL-27Rα ^–/– CD8 ⁺ T cells inhibited CD8 ⁺ T cell proliferation and altered the phenotype and cytokine profile of reconstituted CD8 ⁺ T cells. Our findings uncover what we believe is a novel role of IL-27 in lymphopenia-induced CD8 ⁺ T cell proliferation and suggest that targeting B cell–derived cytokines may increase the efficacy of lymphoablation and improve transplant outcomes.

Abstract

interleukin-27 is induced by antibody-mediated lymphoablation and promotes reconstitution of CD8+ T cells in mouse heart allograft recipients.