T cell memory is comprised of an assortment of phenotypic lineages suited for microbial immunity that may cross-react with allogeneic antigens to drive pathological immune responses. Belatacept is a recently approved post-transplant immunomodulator that inhibits alloreactive T cell responses by blocking the CD28/CTLA-4 pathway and causes fewer toxicities than calcineurin inhibitors (CNI). However, belatacept is associated with an increased incidence and severity of acute rejection episodes early after transplantation, raising the possibility that certain memory T cell subsets are resistant to CD28/CTLA-4 blockade with belatacept. Th17 cells are a pro-inflammatory CD4⁺ lineage that can mediate autoimmune disease, but their relative susceptibility to belatacept is unknown. Restimulation of CD4⁺ memory in a polyclonal restimulation assay significantly inhibited Th1 cells (AVG 79.7 ± 0.405 % of IgG), but increased the frequency of Th17 cells (AVG 139.6 ± 30.72 % of IgG). Following restimulation, Th17 and Th1 memory cells expressed similar amounts of CD28 while Th17 cells significantly upregulated the coinhibitory molecule CTLA-4. Antibody blockade of CTLA-4 resulted in an increase in Th1 and Th17 cells indicating that CTLA-4 functions as a cell intrinsic coinhibitor. These data suggest that Th17 cells might be resistant to belatacept due to greater dependency on coinhibitory signals through CTLA-4, so we investigated whether Th17 memory play a role in rejection of renal transplant recipients treated with belatacept. We found that the frequency of Th17 cells was significantly elevated in belatacept treated patients at the time of rejection (AVG 2.82 ± 0.579%) compared to both belatacept treated patients not experiencing acute rejection (AVG 1.32 ± 0.203%) and patients rejecting on CNI-based regimens (AVG 1.26 ± 0.261%). These data demonstrate that the differential expression of the coinhibitory molecule CTLA-4 affects the function of CD4⁺ memory subsets and provide a potential explanation for the well-described low frequency and proliferative capacity of Th17 cells. Furthermore, these findings provide important insight into the regulation of alloreactive T cell populations by immunomodulatory therapies, and strongly suggest that Th17 cells play a role in early acute rejection in transplant patients treated with belatacept.

Larsen, C.: Other, Bristol-Myers Squibb, Consulting.

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