Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

Abstract

As with studies on the Na + / K + pump24, early results on Na+ /Ca 2 + exchange appeared inconsistent with consecutive ion exchange models (see ref. 5 for review). Our work provides strong support for a consecutive Na +/Ca2+ exchange mechanism a nd should facilitate structure-function studies ofthe cloned Na+ /Ca2+ exchanger. The results of both ion jump experiments and steady-state I ~aCa measurements are inconsistent with Ca2+ translocation involving net negative cha rge movement 8• We conclude from our site-density estimates and I NaCa measurements that max imum exchanger turnover rates are about 5,000 S -I . As alread y proposed for the Na + / K + pumpl 2-17 and rod out er segment Na + / Ca2+ , K + excha nger 2 ,22, voltage-dependence must reside in the binding and release of extracellular Na+ or a closely associated occlusion/ deocclusion reaction. THE al and a2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-ce)) repertoire l -3 , Although the a3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CD8 (refs 4, 5). CD8 is important in the selection of T cells as anti-CD8 antibody injected into perinatal mice interfers with this process 6 • We previously used a hybrid class I molecule with the a 11 a2 domains from L d and the a3 domain from Q7 b and showed that this molecule 718 binds an Ld-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes 7• Expression of this molecule in transgenic mice faUs to negatively select a subpopulation of anti-L d cytotoxic T Iymphocytes. In addition, positive selection of virus-specific L d -restricted cytotoxic T lymphocytes does not occur. We conclude that besides the a1la2 domains of class I, the a3 domain plays an important part in both positive and negative selection of antigen-specific cells.To examine the role of the a3 domain of class I molecules in the responses of alloreactive and antigen-specific cytotoxic T Iymphocytes (CTL), we generated two transgenic mouse strains, C3H.L d and C3H.L Q 3, derived from C3H/ HeJ (H_2 k ) mi ce. C3H .L d express inta ct L d , whereas C3H.LQ3 ex press a n LU molecule whose a3 domain is switched with Q7 b . The Q7 b a 3 domain differs from LU at live residues and in addition has a unique three-amino-acid insert at positions 275-277 (ref. 8). We showed that this molecule (L Q3) binds the same viral peptide as L d but is not recognized by peptide-specific CD8-dependent CTL (ref. 7). Similar observations have been reported with a 3 mutant class I molecules not recognized by CD8-dependent CTL, the defect being due to an alteration in the binding site for C D8 (refs 4,5). 80th L d and L Q3 genes contain the same Qj .0

A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines.

“…Upon interaction of the T-cell antigen receptor (TCR) with major histocompatibility complex-bound peptides, CD4 or CD8 and the associated kinase migrate into the vicinity of the TCR complex, increasing its avidity for the major histocompatibility complex molecule (40,41,61). The signals transduced through the collaboration of CD4 and CD8 with the TCR are critical for selection of the T-cell repertoire during thymic ontogeny and for the activation of mature T cells (1,17,20,24,27,44).Recent evidence suggests that commitment of a thymocyte to express either CD4 or CD8 occurs stochastically and is coordinated with commitment to become a helper or cytotoxic cell, respectively (13). Elucidation of the mechanism involved in the regulation of CD4 and CD8 gene expression is likely to yield important insight into processes involved in the functional differentiation of T-cell subsets.…”

“…Upon interaction of the T-cell antigen receptor (TCR) with major histocompatibility complex-bound peptides, CD4 or CD8 and the associated kinase migrate into the vicinity of the TCR complex, increasing its avidity for the major histocompatibility complex molecule (40,41,61). The signals transduced through the collaboration of CD4 and CD8 with the TCR are critical for selection of the T-cell repertoire during thymic ontogeny and for the activation of mature T cells (1,17,20,24,27,44).…”

In Vitro Correlates ofLd-Restricted Resistance to Toxoplasmic Encephalitis and Their Critical Dependence on Parasite Strain

“…Herein, we examined both of these possibilities using C3H.L d transgenic mice and their wild-type parental control strain, C3H/HeJ. C3H.L d mice have been genetically altered to express the L d gene in addition to their own MHC genes and thus provide a uniquely informative tool for these studies (10). As predicted and as discussed above, these mice are resistant to the development of high numbers of parasites in their brains and toxoplasmic encephalitis (6).…”

Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene.

“…When bone marrow-derived precursor cells begin the process of thymopoiesis, a panel of T-cellspecific genes (TCR, CD2, CD3, and CD4) including CD8a and CD83 are coordinately expressed in a defined temporal sequence (10,32,45). Early in this differentiation pathway, the most immature T cells (CD4-CD8-) progress to step in which the specificity of the TCR repertoire is selected by both positive and negative pressures, a process mediated, in part, by CD8 (1,19,35,70,84). The outcome of this developmental event is the maturation of T cells which express either CD4 or CD8, but not both.…”