Antibody-mediated lymphoablation is a commonly used induction therapy in sensitized transplant recipients. Using murine anti-thymocyte globulin (mATG) in a model of BALB/c (H-2d) to B6 (H-2b) heart transplantation, we reported that the recovery of pathogenic CD8 T cells requires help from depletion-resistant memory CD4 T cells delivered through B cells in CD40/CD154 dependent manner. The goal of this study was to investigate the mechanisms by which B cells mediate CD8 T cell proliferation in lymphopenic hosts.

To test the role of T/B cell cognate interactions, lethally irradiated B cell deficient [mu]MT mice received 1:1 mixture of [mu]MT+WT (control) or [mu]MT+MHC II^−/− BM (B cells lack MHC class II). Resulting BM chimeras received BALB/c heart allografts and were treated with mATG (1 mg i.p. on d. 0 and 4). A similar approach was employed to study the role of MHC I and CD80/86 costimulation. Unexpectedly, the recipients lacking MHC class I, MHC class II or CD80/CD86 expression on B cells had CD8 T cell recovery comparable to controls, indicating that cognate interactions between B cells and either CD4 or CD8 T cells are dispensable for CD8 T cell recovery. In addition, CD4 TCR transgenic T cells reactive to male H-Y antigen supported CD8 T cell recovery in female B6 recipients of either BALB/c male or female heart allografts, further ruling out the antigen contribution to T cell recovery.

To identify B cells that mediate CD4 T cell help for CD8 T cell recovery, we compared B cell subsets in recipients treated with mATG alone or mATG + depleting αCD4 mAb. The CD4 T cell depletion resulted in a decreased ratio of follicular to transitional B cells in mATG treated recipients at d. 12 post-transplant. We next used Nanostring and qPCR to examine gene expression patterns in B cells from mice treated with mATG alone or with mATG + αCD4 mAb. Several cytokines were highly (at least 10-fold) upregulated in B cells during mATG treatment in a CD4 T cell-dependent manner: IL-27, IL-15, IL-1β and IL-6. Of note, cytokines generally associated with non-specific B cell activation such as TNFα and IFNγ were unchanged. Studies are in progress to test the role of identified B cell secreted cytokines in CD8 T cell reconstitution. We propose that targeting specific B cell-derived factors under lymphopenic conditions may increase the efficacy of lymphoablation and improve transplant outcomes while sparing protective immunity.

CITATION INFORMATION: Zwick D, Ayasoufi K, Fan R, Gorbacheva V, Keslar K, Fairchild R, Valujskikh A. B Cell-Derived Cytokines Rather Than T/B Cognate Interactions Mediate CD8 T Cell Reconstitution Following Lymphoablation. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress