*Purpose: Donor-directed HLA antibodies are an important cause of renal allograft injury, but effective therapeutic options to prevent or eliminate donor-specific antibodies (DSA) do not exist. Current therapies primarily target B lineage cells or center around alloantibody removal without focus on T follicular helper (Tfh) cells, the lineage of CD4+ T cells required for the provision of B cell help to generate mature antibody responses. Tfh cells drive de novo antibody formation and can differentiate into memory, but little is known about the role of memory Tfh (mTfh) cells in mediating humoral recall responses in transplantation. Thus, determining whether mTfh cells can accelerate humoral alloresponses and the factors influencing this process will guide strategies to combat HLA antibodies.

*Methods: To examine the mTfh cell alloresponse we utilized a full MHC mismatch BALB/c to B6 murine skin allograft model. Naïve B6 recipients were grafted BALB/c skin, allowed to reject, and then re-grafted BALB/c skin 4-6 weeks after rejection of the primary graft. Graft-draining lymph node (DLN) and serum analyses were performed to measure cellular and humoral recall responses. To determine whether memory responses were mTfh cell-mediated and examine the role of endogenous B cell memory, sorted Balb/c-sensitized congenically-marked Tfh cells were adoptively transferred into naïve B6 mice that were then grafted BALB/c skin and their DLNs examined post-transplant. Tfh cells were also transferred into T cell deficient mice (Tcra KO) to isolate memory from the endogenous primary response.

*Results: DLN analyses of Balb/c sensitized mice following skin graft re-challenge revealed accelerated Tfh cell, germinal center (GC) B cell and DSA responses compared to the primary response in skin-grafted naïve controls. These rapid memory responses were alloreactive in that they occurred upon rechallenge with Balb/c but not syngeneic B6 skin grafts. Memory Tfh cells adoptively transferred into naïve B6 mice without B cell memory exhibited rapid differentiation into effector Tfh cells compared to naïve CD4+ T cell controls 5 days after Balb/c skin-grafting. Transfer of mTfh cells into Tcra KO mice incapable of a primary T cell response and devoid of B cell memory also resulted in accelerated effector Tfh cell differentiation.

*Conclusions: In sum, mTfh cells independent of B cell memory and primary T cell responses exhibit accelerated effector Tfh cell differentiation following repeat alloantigen exposure via transplantation. These findings support further elucidating the role of mTfh cells in recall humoral alloresponses, as their anamnestic qualities could have important diagnostic and therapeutic clinical implications.

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