A Three-Cell Cluster Hypothesis for Noncognate T-B Collaboration via Direct T Cell Recognition of Allogeneic Dendritic Cells1

Abstract

In this article, we propose that T cell help for B cells can occur via an unusual three-cell cluster, with recipient CD4+ T helper cells interacting via direct allorecognition with donor dendritic cell class II MHC antigens, recipient B cells interacting with MHC class I (or any other) antigen on the donor dendritic cell surface, and noncognate (i.e., antigen nonspecific) T-B collaboration. In this noncognate pathway, antigen processing by B cells is not required and T cell help is potent because of the high precursor T cell frequency for direct recognition of allogeneic class II MHC molecules. The data supporting this hypothesis are: 1. LEW rat strain recipients of interstitial dendritic cell-free (DAxLEW)F1 kidney allografts were shown to have no detectable antibody to donor class I MHC antigens at day 7 after grafting. By contrast, LEW recipients of normal (DAxLEW)F1 kidneys had strong antibody responses. 2. Consistent wih important role for donor dendritic cells in the early antibody response to donor class I MHC antigens was the finding that it was dependent on donor class II MHC antigens. PVG recipients, previously immunized with pure DA RT1.B class II MHC antigens, had virtually no antibody response to the class I MHC antigens of DA kidney allografts. 3. We confirmed the low and high responder status of PVG and LEW rats, respectively, to DA class I antigens by studying antibody responses to pure DA class I antigens. However, PVG and LEW recipients of DA kidney allografts did not differ in their antibody response to the donor DA class I MHC antigens. This is consistent with this response not requiring the processing and presentation of DA class I antigen by PVG recipients. 4. LEW recipients of interstitial dendritic cell-free (DAxLEW)F1 kidney allografts did eventually develop a strong antibody response to DA class I antigens, but this was delayed by several weeks. That this delayed antibody response was probably mediated by conventional T-B collaboration and that T help was rate limiting in this situation, was demonstrated by immunizing LEW recipients with a DA class I peptide. This markedly accelerated the kinetics of the antibody response to the dendritic cell-free (DAxLEW)F1 kidneys.

Germinal Center Alloantibody Responses Are Mediated Exclusively by Indirect-Pathway CD4 T Follicular Helper Cells

“…This ‘three-cell cluster model’ (Fig. 1 B ) was first suggested by Fabre, who noted that blockade of donor MHC class II alloantigen abrogated anti-MHC class I alloantibody responses to a rat heart graft (19).…”

“…Although previous publications, including our own, have concluded that direct-pathway CD4 T cells cannot provide help for class-switched alloantibody responses (18, 31, 63), we felt it important to re-examine this concept, because as discussed in the introduction and as suggested by Fabre’s findings (19, 64), these studies may obscure a role for direct-pathway help either because the B cell compartment lacked MHC class II expression (18) or because non-vascularised skin graft models were studied (31). Of more significance, definitive rebuttal of direct-pathway help for alloantibody production requires specific examination of the memory CD4 T cell subset.…”

“…Transplantation is unusual because CD4 T cells can recognise alloantigen through two distinct pathways (14-17): in the direct pathway, which is unique to transplantation, alloantigen is recognised as intact protein on the surface of donor APCs; whereas in the indirect pathway, which is akin to recognition of conventional protein antigen, alloantigen is first processed by recipient APCs and then presented as peptide fragments in the context of host MHC class II. Which of these two pathways of alloreactive CD4 T cell activation is responsible for providing help for alloantibody production remains controversial (18, 19), not least because the humoral alloimmune response is complex and composed of several anatomically-distinct components. Thus, simple assay of serum alloantibody may fail to reveal subtle yet important differences in how the helper CD4 T cell allorecognition pathway impacts on the various constituent arms.…”

Unlinked Memory Helper Responses Promote Long-Lasting Humoral Alloimmunity

“…In the direct pathway, which is unique to transplantation, alloantigen is recognised intact on the surface of donor APCs, whereas in the indirect pathway, alloantigen is processed and presented as peptide fragments by recipient APCs for self-restricted recognition. One study has suggested that alloreactive B cells can receive help from direct-pathway CD4 T cells (15), but this has remained controversial (16), and we have demonstrated recently that only indirect-pathway CD4 T cells act as T follicular helper (T FH ) cells for generating long-lasting, class-switched alloantibody (17).…”