Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture.

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The contribution of secondary lymphoid tissue homing central memory T cells (TCM) and peripheral tissue homing effector memory T cells (TEM) to allograft rejection is not known. We tested whether TEM is the principal subset responsible for allograft rejection due to the non-lymphoid location of target antigens. Skin allograft rejection was studied after transferring either CD8 TCM or TEM to wild type mice and to mice that lack secondary lymphoid tissues. We found that CD8 TCM and TEM were equally effective at rejecting allografts in wild type hosts. However, CD8 TEM were significantly better than TCM at rejecting allografts in the absence of secondary lymphoid tissues. CD8 TCM were dependent upon secondary lymphoid tissues more than TEM for optimal differentiation into effectors that migrate into the allograft. Recall of either CD8 TCM or TEM led to accumulation of TEM after allograft rejection. These findings indicate that either CD8 TCM or TEM mediate allograft rejection but TEM have an advantage over TCM in immune surveillance of peripheral tissues, including transplanted organs.

Secondary lymphoid tissues are the hub of adaptive immune responses wherein rare cognate lymphocytes encounter dendritic cells bearing antigen from peripheral tissues and differentiate into effector and memory cells that eliminate antigen. It is accepted that immune responses against microbial and tumor antigens are initiated within secondary lymphoid tissues. There is less agreement on whether the same principle applies to immune responses to a transplanted organ because an allograft expresses foreign major histocompatibility complex and contains donor antigen presenting cells that could activate T cells directly in situ leading to rejection. Recent studies confirm that although naïve T cells can be primed within the allograft, their differentiation to effect rejection is dependent on secondary lymphoid tissues. Antigen-experienced memory T cells, unlike Naïve T cells, function largely independent of secondary lymphoid tissues to cause allograft rejection. In an alloimmune response, secondary lymphoid tissues support not only immune activation but also immune regulation essential for allograft survival. Here, we will review recent findings and discuss the role of secondary lymphoid tissues in primary and memory alloimmune responses.

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B cells help alloreactive T cells to differentiate into memory T cells. Since B cells express TLRs, we asked whether MyD88-mediated activation of B cells is required for T cell activation and differentiation to memory T cells. Methods: Irradiated μMTCD45.1 mice were transplanted with bone marrow cells from μMTCD45.1 and wtCD45.2 (μMT+wt) or μMTCD45.1 and MyD88-/-CD45.2 (μMT+MyD88-/-). Differences in congenic background allowed us to confirm that following reconstitution, MyD88 deficiency was essentially restricted to B cells. μMT+MyD88-/- and μMT+wt received Balb/c skin transplants. Results: Rejection of allografts was comparable between μMT+MyD88-/- and μMT+wt chimeras (MST=18 days). μMT+MyD88-/- recipients showed 3-fold more alloreactive IFNγ+ CD4 and CD8 effector T cells when compared to μMT+wt mice at day 14 (p<0.05). IL-10+ B cells were diminished (p<0.005) in μMT+MyD88-/- than in μMT+wt chimeras. CD8 memory precursor T cells (CD44hi CD62Llo CD127hi) in μMT+MyD88-/- showed predominantly Bcl2lo expression in both KLRG1lo memory precursor effector cell (MPEC) and KLRG1hi short-lived effector cell (SLEC) populations. Consistent with these findings, fewer alloreactive CD4 and CD8 IFNγ+ memory T cells were seen in μMT+MyD88-/- (p<0.005) resulting in impaired memory recall (MST = 27 vs. 15 days, p < 0.005) than in μMT+wt chimeras. Conclusions: Intrinsic MyD88-dependent B cell functions are important for alloreactive T cell differentiation into long-lived memory T cells.

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