Human CD8 transgene regulation of HLA recognition by murine T cells.

Abstract

SummaryA series of human CD8 transgenic (hCD8 Tg) mice with differential expression in the thymus and periphery were produced to investigate CD8 coreceptor regulation of repertoire selection and T cell responses. Expression of hCD8 markedly enhanced responses to both HLA class I molecules and hybrid A2/K b molecules providing functional evidence for a second interaction site, outside of the ct3 domain, which is essential for optimal coreceptor function. Peripheral T cell expression ofhCD8 was sufficient to augment responsiveness to HLA class I, as hCD8 Tg mice which lacked thymic expression responded as well as mice expressing hCD8 in the thymus and periphery. Both murine CD8 + and CD4 + T cells expressing hCD8 transgenes exhibited markedly enhanced responses to foreign HLA class I, revealing the ability of T cell receptor repertoires selected on either murine class I or class II to recognize human class I major histocompatibility complex (MHC). In contrast to recognition of foreign class I, thymic expression of hCD8 transgenes was absolutely required to enhance recognition of antigenic peptide restricted by self-HLA class I. Thus, our studies revealed disparate requirements for CD8 coreceptor expression in the thymus for selection of a T cell repertoire responsive to foreign MHC and to antigenic peptides bound to self-MHC, providing a novel demonstration of positive selection that is dependent on human CD8.T cells have evolved to recognize foreign antigens displayed on the cell surface in association with class I or class II MHC proteins. The T cell receptor ligand being recognized is a binary MHC-peptide complex. However, TCR binding to MHC peptide is generally not sufficient for activation of T cells. Functional recognition usually requires concurrent binding of class I or class II MHC-peptide complexes by TCR and CD8 or CD4 coreceptors, respectively (1-4). Whereas the molecular basis for TCR binding to the class I MHC-peptide complexes involves specific interactions with peptide bound by the 0el, ct2 domains of MHC molecules (5, 6), CD8 coreceptors interact with a nonpolymorphic region within the % domain of class I MHC proteins (7,8 class I MHC proteins generally express CD8 coreceptors, whereas T cells that express CD4 coreceptors generally recognize antigenic peptide presented by class II MHC proteins (reviewed in [91).The interaction of TCR and coreceptors with MHCpeptide ligands is essential for the initiation ofthymic selection, alloreactivity, and recognition of antigenic peptide presented by self-MHC-restricting elements. Furthermore, development of immune cells capable of mediating these functional responses requires expression of both TCR (10, 11) and coreceptors (12, 13). However, it has been difficult to assess the relative contribution of the TCI~ and coreceptors in directing the specificity of these functional responses. We generated human CD8 transgenic (hCD8 Tg) 1 mice to determine the specific affects of CD8 coreceptor binding to MHC class I on positive selection and peripheral T cell respon...

In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8+ T Cells

“…Thus, unless provided with an appropriate coreceptor molecule, the inherent specificity of a TCR for either a class I or a class II MHC molecule is insufficient to effect T cell activation. Ectopic expression of a CD8 transgene has revealed class I alloreactivity by CD4 ϩ T cells (42,43), and the expression of a CD4 transgene has demonstrated the inherent class II specificity among TCRs expressed by CD8 ϩ T cells (44,45). These findings imply that during development some DP thymocytes bear TCRs that can recognize and are susceptible to positive and negative selection by both class I and class II MHC molecules.…”

Opposing chemokine gradients control human thymocyte migration in situ

“…Human CD8 and CD4 can interact with mouse MHC class I and MHC class II, respectively, and there are indications that human thymocytes can undergo positive selection on mouse MHC (21)(22)(23)(49)(50)(51). However, human thymocytes express both MHC class I and MHC class II, and there is evidence that some positive selection in humanized mice occurs via human thymocyte-thymocyte interactions (52).…”

Human MHC Class I Transgenic Mice Deficient for H2 Class I Expression Facilitate Identification and Characterization of New HLA Class I-Restricted Viral T Cell Epitopes

“…Although the anti-NP366 -374/H2 b response is dominated by V␤8.3 ϩ cells, the anti-NP383-391/HLA-B27 hyb response is mediated mainly by V␤8.1 ϩ cells. association of fully native HLA class I H chains with m␤ 2 m (15), replacement of the human class I ␣3 domain with mouse ␣3 to overcome inefficient interactions with m␤ 2 m and mouse CD8 (14,16), breeding of the HLA Tg onto apparently more favorable mouse H2 backgrounds (33), introduction of a Tg construct encoding linked ␤ 2 m and HLA onto a m␤ 2 m-deficient background to reduce surface expression of H2 class I (34), and coexpression of a human CD8 Tg along with Tg HLA to facilitate species-specific CD8 interactions (35). Although these efforts have been instructive, questions still remain about what form this type of model should take to optimize efficient and specific function of the human MHC molecules.…”