Functional CD8⁺but not CD4⁺T cell responses develop independent of thymic epithelial MHC

Abstract

The role of nonthymic epithelial (non-TE) MHC in T cell repertoire selection remains controversial. To analyze the relative roles of thymic epithelial (TE) and non-TE MHC in T cell repertoire selection, we have generated tetraparental aggregation chimeras (B6-nude7BALB͞c and B67BALB͞c-nude) harboring T and B cells from both parents, whereas TE cells originated exclusively from the non-nude donor. These chimeras mounted protective virus-specific TE and non-TE MHC-restricted T cell responses. To further evaluate whether non-TE MHC alone was sufficient to generate a functional T cell repertoire, we generated tetraparental aggregation chimeras lacking MHC class II (B6-nude7MHCII ؊/؊ ) or both MHC molecules (B6-nude7MHCI ؊/؊ II ؊/؊ ) on TE cells, but not on cells of B6-nude origin. Chimeras with MHC-deficient TE cells mounted functional virus-specific CD8 ؉ but not CD4 ؉ T cell responses. Thus, maturation of functional CD4 ؉ T cell responses required MHC class II on thymic epithelium, whereas CD8 ؉ T cells matured in the absence of TE MHC. Although studies with nude mice reconstituted with a fully allogeneic thymus graft showed almost exclusive restriction to nude MHC alone, these studies were also not accepted because of suspected rescue of nude thymic rudiment (18). More recently, however, the availability of new tools and mice has allowed the controversial issue of the role of non-TE versus TE MHC in T cell repertoire selection to be readdressed. We had generated tetraparental aggregation chimeras from thymus-deficient nude mice and T and B celldeficient Rag Ϫ/Ϫ mice (19). In these Rag Ϫ/Ϫb 7nude d tetraparental aggregation chimeras TE cells were exclusively of Rag Ϫ/Ϫ H-2 b origin; however, T and B cells were exclusively of nude H-2 d origin. After infection of these chimeras with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), the MHC restriction and functionality of T cells were analyzed. Protective LCMV-specific CD8 ϩ T cell responses restricted to TE and non-TE MHC were detected in all chimeras tested. In addition, CD4 ϩ T cells restricted to non-TE MHC were present and functional as shown by the presence of high titers of CD4 ϩ T cell-dependent VSV-specific neutralizing antibodies comparable to those present in control mice. However, concerns emerged that T cells restricted to nude MHC in these chimeras might have had a survival advantage in the periphery over TE MHC-restricted T cells. It is well known that after leaving the thymus mature T cells are able to survive only in the periphery when their TCR remain in continuous interaction with TCR-restricting MHC molecules (20)(21)(22). In the periphery, mature T cells will primarily be in contact with their surrounding T and B cells, which in the Rag Ϫ/Ϫb 7nude d chimeras exclusively express nude MHC. Even if the nude MHC-restricted T cells after leaving the thymus were initially a minor population, in the periphery these T cells might have a survival advantage over the initially more numerous TE MHC-restricted T cells.Therefore,...

Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation

“…We would therefore hypothesize that nonmyeloablatively conditioned chimeric humans would be immunocompetent to respond to infectious challenge. It is likely that there are sufficient numbers of professional and nonprofessional antigen-presenting cells remaining to allow robust immunocompetence and tolerance in the nonmyeloablatively conditioned subjects with high levels of donor chimerism (33,34). It is of note that all severe adverse events experienced by the 8 subjects occurred while they were on conventional maintenance immunosuppression.…”

Why T Cells of Thymic Versus Extrathymic Origin Are Functionally Different

“…Why are extrathymic CD4 T cells totally unfit to generate protective responses when confronted with pathogens? In tetraparental aggregation chimeras, thymusderived CD4 T cells positively selected on hemopoietic cells are unable to generate functional antiviral responses (62). We therefore posit that positive selection by thymic epithelial cells is absolutely required to produce functional CD4 T cells.…”

Peripheral T cells in the thymus: have they just lost their way or do they do something?

“…Curiously, selection on hematopoietic cells has in the past been more frequently demonstrated for class I MHC‐restricted cells, that is for CD8 + T cells. Thus, there may be a dichotomy for CD4 + and CD8 + cells 54 . Apart from this, only a fraction of the TCRs normally selected on cTEC may actually be selectable on hematopoietic cells.…”