Introduction: : In our previous work we have shown that donor CD4 T cells within heart grafts initiate anti-nuclear autoantibody responses. Here we clarify the contribution of host CD4 T cells to progression and maintenance of the response.

Methods: Bm12 heart grafts were transplanted into wild type (WT), T-cell deficient (TCR-/-) or SAP-/- B6 recipients that lack T follicular helper (TFH) cells. Germinal centres (GCs) were quantified by calculating percentages of PNA / GL7+ve splenic B cell follicles, and allograft vasculopathy (AV) and graft rejection monitored.

Results: Bm12 heart allografts developed progressive AV when transplanted into WT recipients and provoked long lasting GC (68±3% PNA+ve splenic B cell follicles) autoantibody responses, with late generation of anti-vimentin autoantibody (relative anti-vimentin IgG levels were 77±3 at week 7 vs 287±2 at week 15, p= .007) evident. Depleting CD4 T cells in the donor abrogated autoantibody production and resulted in minimal AV (12±8% luminal stenosis). In contrast, transplantation into TCR-/- recipient triggered autoantibody responses, but GC activity was not observed, and heart grafts survived indefinitely (MST >100d) and ameliorated AV (1±2% luminal stenosis). Critically, heart grafts transplanted into SAP-/- recipients triggered autoantibody generation, but neither GC activity nor late anti-vimentin responses were detectable and grafts developed only minimal AV (% luminal stenosis was 10±8 in SAP-/- recipients vs 74±1 in WT, p=0.02) and survived significantly longer (MST was 91d in SAP-/- vs 56d in WT, p=0.04) . In support of the role of GC autoantibody responses in mediating allograft vasculopathy, in a wound-induced endothelial cell (EC) migration assay, cultured bm12 endothelial cells showed fivefold less migration upon addition of serum from SAP-/- recipients than when serum from WT recipients was added.

Conclusion: Our results demonstrate that donor passenger CD4 T cells within an allograft can trigger recipient autoantibody responses, but graft rejection is dependent upon progression to a GC response, with essential help for its development provided by host TFH cells.

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