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

Abstract

The durable alloantibody responses that develop in organ transplant patients indicate long-lived plasma cell output from T-dependent germinal centres (GCs), but which of the two pathways of CD4 T cell allorecognition are responsible for generating allospecific T follicular helper (TFH) cells remains unclear. This was addressed by reconstituting T-cell deficient mice with monoclonal populations of TCR-transgenic CD4 T cells that recognised alloantigen only as conformationally-intact protein (direct pathway) or only as self-restricted allopeptide (indirect pathway), and then assessing the alloantibody response to a heart graft. Recipients reconstituted with indirect-pathway CD4 T cells developed long-lasting IgG alloantibody responses, with splenic GCs and allospecific bone marrow plasma cells readily detectable 50 days after heart transplantation. Differentiation of the transferred CD4 T cells into TFH cells was confirmed by follicular localisation and by acquisition of signature phenotype. In contrast, IgG alloantibody was not detectable in recipient mice reconstituted with direct-pathway CD4 T cells. Neither prolongation of the response by preventing NK cell killing of donor dendritic cells, nor prior immunisation to develop CD4 T cell memory altered the inability of the direct-pathway to provide allospecific B cell help. CD4 T cell help for GC alloantibody responses is provided exclusively via the indirect-allorecognition pathway.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…[5][6][7] The requirement of T-cell help for B-cell antibody production was first described in the late sixties. 8,9 CD4 Tfh cells of the secondary lymphoid organs are now recognized as the immune cells that are responsible for orchestrating the molecular interactions that provide help to B cells.…”

Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans

“…5 Therefore, we examined the presence of splenic Tfh cells in cGVHD mice because Tfh cell support is necessary for GC formation. [17][18][19] Spleens harvested from mice with cGVHD demonstrated an increased presence of CD4 1 cells in peanut agglutininpositive GC areas compared with non-GVHD mice, co-localizing to regions of high PD-1 expression ( Figure 1A). Localization of CD4 1 cells to the GC by the chemical gradient chemokine ligand CXCL13 binding with its receptor CXCR5 is a hallmark of Tfh cells.…”

CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection

“…This importance partly reflects the unique ability of indirect-pathway CD4 T cells to act as helper T cells for generating sophisticated alloantibody responses (10), but it is now also clear that effective cytotoxic CD8 T-cell responses can be generated when CD4 T-cell help is restricted exclusively to the indirect pathway (11). This observation is surprising, because the delivery of indirect-pathway T-cell help is only readily explained by postulating the unlikely formation of a cumbersome four-cell cluster, comprising CD4 and CD8 T lymphocytes and both recipient and donor APC (Fig.…”