Antibody-suppressor CXCR5+CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice

Abstract

CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody‐mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H‐2b) were transplanted with A/J kidneys (H‐2a); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+CD8+ T cells and CD8‐mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four‐fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six‐fold in CCR5 KO recipients. ACT with alloprimed CXCR5+CD8+ T cells (but not alloprimed CXCR5−CD8+ or third‐party primed CXCR5+CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.

CXCR5+CD8+ T Cell–Mediated Suppression of Humoral Alloimmunity and AMR in Mice Is Optimized With mTOR and Impaired With Calcineurin Inhibition

“…Additionally, alloprimed CXCR5 + CD8 + T cells from CCR5 KO recipients have a 30% lower capacity to kill antibody-producing IgG + B cells in vitro compared with WT CXCR5 + CD8 + T cells. 19 ACT with CD8 + T Ab-supp cells in high alloantibody-producing CCR5 KO KTx recipients significantly reduces alloantibody production (4.6-fold reduction of day 14 posttransplant alloantibody titer) and ameliorates AMR pathology (2.4-fold reduction in day 14 composite AMR pathology score). Furthermore, ACT-mediated reduction of alloantibody titer and improved pathology correlates with enhanced allograft survival in murine KTx recipients (median survival time = day 52 versus day 15 without ACT).…”

“…These results complement our prior studies reporting the antigen specificity of alloprimed CXCR5 + CD8 + T-cell effector function. 18,19 We next examined the expression of the cytotoxic effector molecules previously reported to be important for antibody-suppressor CXCR5 + CD8 + T function. 33 To do this, CXCR5 + CD8 + T cells were retrieved from alloprimed GFP mice for adoptive transfer into CCR5 KO KTx recipients.…”

“…19 CD8 + T Ab-supp cell effector functions are allospecific because third party-primed CXCR5 + CD8 + T cells do not mediate these in vivo antibody-suppressor functions. 18,19 The translational relevance of these findings is supported by the identification of CXCR5 + interferon (IFN)-γ + CD8 + T cells in the peripheral blood of human KTx recipients. Furthermore, we reported that KTx recipients with an increased quantity of circulating CXCR5 + IFN-γ + CD8 + T cells had lower incidence of de novo DSA production, rejection, and graft loss at 1 y posttransplant that were not attributable to differences in immunosuppression or clinical characteristics.…”

Biology and clinical relevance of follicular cytotoxic T cells

“…They also used human CXCR5 murine leukemia virus (MuLV)-based retroviral expression vector to insert CXCR5 gene to CD8 + T cells, and the expression of PD-1 was downregulated, that could be associated with the homing of remodeled-Tfc cells into B cell follicles (22). As for the potential therapeutic modalities in antibody mediated disease, Zimmerer et al (83) found that after receiving adoptive therapy with alloprimed CXCR5 + CD8 + T cells, the alloantibody titer in kidney transplant mice was reduced, which ameliorated antibody-mediated rejection and prolonged allograft survival.…”

“…As for the potential therapeutic modalities in antibody mediated disease, Zimmerer et al. ( 83 ) found that after receiving adoptive therapy with alloprimed CXCR5 + CD8 + T cells, the alloantibody titer in kidney transplant mice was reduced, which ameliorated antibody-mediated rejection and prolonged allograft survival.…”