Activation of CD8+ cytotoxic T lymphocytes typically begins with recognition of class I MHCpeptide complexes by the TCR and CD8 as a coreceptor. In its coreceptor role, CD8 binds the same class I-peptide antigen complex as the TCR, enhancing the strength of TCR-class I interaction. Subsequent to initial TCR engagement, CD8 acts as an accessory molecule by binding any properly conformed class I molecules on the target cell surface, leading to CD8-mediated adhesion and cosignaling functions. We expressed and isolated a number of mutant class I molecules in which one or more acidic or polar residues in the class I § 3 domain CD loop and D strand region, or § 2 domain were altered. Using solid phase CTL adhesion and degranulation assays with isolated class I molecules, we demonstrate that multiple acidic residues in the § 3 domain, although involved in CD8 coreceptor interaction, are not required for TCR-activated CD8 accessory interactions. Instead, we show that Q226, a polar group on the end of the CD loop, is required for TCR-activated CD8 accessory functions. These results indicate that CD8 coreceptor and accessory interactions differ substantially and suggest that TCR activation results in changes that alter the structural constraints for CD8 accessory interactions.
Improving prediction of outcomes in CKD patients with either native or transplant kidneys remains an important goal. Increasingly sophisticated biomarkers may potentially identify targets for clinical research, improve the nature and timing of therapeutic interventions, and guide resource allocation.
The CD8 receptor plays a central role in the recognition and elimination of virally infected and malignant cells by cytolytic CD8+ T cells. In conjunction with the TCR, the CD8 coreceptor binds Ag-specific class I MHC (MHC-I) molecules expressed by target cells, initiating signaling events that result in T cell activation. Whether CD8 can further function as an adhesion molecule for non-Ag MHC-I is currently unclear in humans. In this study, we show that in human CD8+ T cells, TCR complex signaling activates CD8 adhesion molecule function, resulting in a CD8 interaction with MHC-I that is sufficient to maintain firm T cell adhesion under shear conditions. Secondly, we found that while CD8 adhesive function was triggered by TCR complex activation in differentiated cells, including in vitro generated CTL and ex vivo effector/memory phenotype CD8+ T cells, naive CD8+ T cells were incapable of activated CD8 adhesion. Lastly, we examine the kinetics of, and signaling for, activated CD8 adhesion in humans and identify notable differences from the equivalent CD8 function in mouse. Activated CD8 adhesion induced by TCR signaling may contribute to the more rapid and robust elimination of pathogen-infected cells by differentiated CD8+ T cells.
Ly-49 receptors regulate mouse natural killer cell functions. Members of the polymorphic Ly-49 multigene family recognize specific alleles of major histocompatibility complex class I (MHC I) or MHC I-like proteins. Previous studies have provided insight into the nature of Ly-49A and -C interaction with their high-affinity MHC I ligands, H-2Dd and Kb, respectively. Unlike Ly-49C, recognition of MHC I by Ly-49A is regulated in part by residues within the beta4-beta5 loop of its ectodomain. Ly-49A and -G are within the same Ly-49 subfamily, and both receptors recognize Dd. However, there have been no studies that define specific sites on Ly-49G that mediate class I MHC recognition. The Ly-49G receptors of different inbred mouse strains can differ as a result of amino acid polymorphisms within their ectodomains. In this report, we have generated a novel antibody, CK-1, which recognizes Ly-49G(B6) and a Ly-49G(B6)-like receptor, Ly-49M(nonobese diabetic), but not Ly-49G(BALB/c). By exploiting the differences within ectodomains of C57BL/6 and BALB/c Ly-49G allele products, we identified epitopes recognized by the Ly-49G-specific antibodies CK-1 and Cwy-3, whose epitopes mapped within the beta4-beta5 loop and the beta1 strand, respectively, and were nonoverlapping. Although both antibodies specifically recognized the Ly-49G(B6) ectodomain, Cwy-3 was unable to block its interaction with MHC I, and CK-1 significantly inhibited it. The importance of residues within the beta4-beta5 loop in Ly-49G recognition demonstrates that its interaction with MHC I is similar to that of Ly-49A but not Ly-49C.
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