scholarly journals Identification of a recombinogenic major histocompatibility complex Q gene with diverse alleles.

1993 ◽  
Vol 177 (6) ◽  
pp. 1803-1807 ◽  
Author(s):  
M K Cullen ◽  
L A Lapierre ◽  
K V Kesari ◽  
J Geliebter
Keyword(s):  
T Cell ◽  
Structural Diversity ◽  
Cell Receptor ◽  
Sequence Diversity ◽  
Class I ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Complex ◽  
Q Gene ◽  
Selection Of

Structural diversity enables class Ia molecules to present a diverse repertoire of peptides to the T cell receptor. This diversity is thought to be generated by recombinations between class I genes. We have found that two class Ib Q2 alleles exhibit extremely high sequence diversity, even higher than class Ia alleles. Clustered nucleotide differences between Q2b and Q2k suggest that this sequence diversity was generated by microrecombinations between Q2 genes and other class I genes. The relatively high expression of Q2b in the thymus may be significant and perhaps suggests a novel role for a Q2b product in the education and selection of the T cell repertoire.

scholarly journals T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire.

1991 ◽  
Vol 174 (6) ◽  
pp. 1371-1383 ◽  
Author(s):  
J L Casanova ◽  
P Romero ◽  
C Widmann ◽  
P Kourilsky ◽  
J L Maryanski
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Lymphocyte ◽  
Plasmodium Berghei ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Allelic Exclusion ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Complex

We report here the first extensive study of a T cell repertoire for a class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) response. We have found that the T cell receptors (TCRs) carried by 28 H-2Kd-restricted CTL clones specific for a single Plasmodium berghei circumsporozoite nonapeptide are highly diverse in terms of V alpha, J alpha, and J beta segments and aminoacid composition of the junctional regions. However, despite this extensive diversity, a high proportion of the TCRs contain the same V beta segment. These results are in contrast to most previously reported T cell responses towards class II MHC-peptide complexes, where the TCR repertoires appeared to be much more limited. In our study, the finding of a dominant V beta in the midst of otherwise highly diverse TCRs suggests the importance of the V beta segment in shaping the T cell repertoire specific for a given MHC-peptide complex. As an additional finding, we observed that nearly all clones have rearranged both TCR alpha loci. Moreover, as many as one-third of the CTL clones that we analyzed apparently display two productive alpha rearrangements. This argues against a regulated model of sequential recombination at the alpha locus and consequently raises the question of whether allelic exclusion of the TCR alpha chain is achieved at all.

scholarly journals Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection

Nature ◽  
2010 ◽  
Vol 465 (7296) ◽  
pp. 350-354 ◽  
Author(s):  
Andrej Košmrlj ◽  
Elizabeth L. Read ◽  
Ying Qi ◽  
Todd M. Allen ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Hla Class I ◽  
Class I ◽  
Thymic Selection ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Selection Of

scholarly journals Highly Restricted T Cell Repertoire Shaped by a Single Major Histocompatibility Complex–Peptide Ligand in the Presence of a Single Rearranged T Cell Receptor β Chain

1998 ◽  
Vol 188 (5) ◽  
pp. 897-907 ◽  
Author(s):  
Yoshinori Fukui ◽  
Osamu Hashimoto ◽  
Ayumi Inayoshi ◽  
Takahiro Gyotoku ◽  
Tetsuro Sano ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Positive Selection ◽  
Peptide Ligand ◽  
T Cell Repertoire ◽  
Major Histocompatibility ◽  
Cell Repertoire ◽  
Histocompatibility Complex ◽  
Self Peptides ◽  
Selection Of

The T cell repertoire is shaped by positive and negative selection of thymocytes through the interaction of α/β-T cell receptors (TCR) with self-peptides bound to self-major histocompatibility complex (MHC) molecules. However, the involvement of specific TCR-peptide contacts in positive selection remains unclear. By fixing TCR-β chains with a single rearranged TCR-β irrelevant to the selecting ligand, we show here that T cells selected to mature on a single MHC–peptide complex express highly restricted TCR-α chains in terms of Vα usage and amino acid residue of their CDR3 loops, whereas such restriction was not observed with those selected by the same MHC with diverse sets of self-peptides including this peptide. Thus, we visualized the TCR structure required to survive positive selection directed by this single ligand. Our findings provide definitive evidence that specific recognition of self-peptides by TCR could be involved in positive selection of thymocytes.

scholarly journals Role of the Multiple T Cell Receptor (TCR)-ζ Chain Signaling Motifs in Selection of the T Cell Repertoire

1997 ◽  
Vol 185 (5) ◽  
pp. 893-900 ◽  
Author(s):  
Elizabeth W. Shores ◽  
Tom Tran ◽  
Alexander Grinberg ◽  
Connie L. Sommers ◽  
Howard Shen ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Selection Process ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Ligand Interaction ◽  
Competent Self ◽  
Selection Of

Immature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC–restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR–ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-γ, -δ, -ε, and ζ) that contain either one (CD3-γ, -δ, -ε) or three (-ζ) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR-ζ chain ITAMs in thymocyte selection, transgenes encoding α/βTCRs with known specificity were bred into mice in which ζ chains lacking one or more ITAMs had been genetically substituted for endogenous ζ. A direct relationship was observed between the number of ζ chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.

scholarly journals Unresponsiveness to a self-peptide of mouse lysozyme owing to hindrance of T cell receptor-major histocompatibility complex/peptide interaction caused by flanking epitopic residues.

1996 ◽  
Vol 183 (2) ◽  
pp. 535-546 ◽  
Author(s):  
K D Moudgil ◽  
I S Grewal ◽  
P E Jensen ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Response ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Complex ◽  
Critical Residues ◽  
Mouse Lysozyme

A self-peptide containing amino acid residues 46-61 (NRGDQSTDYGIFQINSR) of mouse lysozyme (ML) (p46-61, which binds strongly to the A(k) molecule but does not bind to the E(k) molecule), can induce a strong proliferative T cell response in CBA/J mice (A[k], E[k]) but no response at all in B10.A(4R) and CBA/J mice. The critical residues within p46-59 are immunogenic in both B10.A(4R) and CBA/J mice. The critical residues within p46-61 reside between amino acid positions 51 and 59. T cells of B10.A(4R) mice primed with the truncated peptides in vivo cannot be restimulated by p46-61 in vitro. This suggests that T cell receptor (TCR) contact (epitopic) residue(s) flanking the minimal 51-59 determinant within p46-61 hinder the interaction of the p46-61/A(k) complex with the appropriate TCR(S), thereby causing a lack of proliferative T cell response in this mouse strain. Unlike B10.A(4R) mice, [B10.A(4R) x CBA/J]F1 mice responded vigorously to p46-61, suggesting that thymic APC of B10.A(4R) mice do not present a self ligand to T cells resulting in a p46-61-specific hole in the T cell repertoire in B10.A(4R) or the F1 mice. Moreover, APC from B10.A(4R) mice are capable of efficiently presenting p46-61 to peptide-specific T cell lines from CBA/J mice. The proliferative unresponsiveness of B10.A(4R) mice to p46-61 is not due to non-major histocompatibility complex genes because B10.A mice (A[k], E[k]) respond well to p46-61. Interestingly, B10.A(4R) mice can raise a good proliferative response to p46-61 (R61A) (in which the arginine residue at position 61 (R61L/F/N/K), indicating that R61 was indeed responsible for hindering the interaction of p46-61 with the appropriate TCR. Finally, chimeric mice [B10.A(4R)-->B10.A] responded vigorously to p46-61, suggesting that thymic antigen presentation environment of the B10.A mouse was critical for development of a p46-61-reactive T cell repertoire. Thus, we provide experimental demonstration of a novel mechanism for unresponsiveness to a self peptide, p46-61, in the B10.A(4R) mouse owing to hindrance: in this system it is the interaction between the available TCR and the A(k)/p46-61 complex, which is hindered by epitopic residue(s) within p46-61. We argue that besides possessing T cells that are hindered by R61 of p46-61, CBA/J and B10.A mice have developed an additional subset of T cells bearing TCRs which are not hinderable by R61, presumably through positive selection with peptides derived from class II E(k), or class I D(k)/D(d) molecules. These results have important implications in self tolerance, shaping of the T cell repertoire, and in defining susceptibility to autoimmunity.

scholarly journals T cell receptor-mediated recognition of self-ligand induces signaling in immature thymocytes before negative selection.

1992 ◽  
Vol 176 (2) ◽  
pp. 459-468 ◽  
Author(s):  
R Abe ◽  
Y Ishida ◽  
K Yui ◽  
M Katsumata ◽  
T M Chused
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antigen Presenting ◽  
Self Antigen ◽  
Selection Of

Shaping of the T cell repertoire by selection during intrathymic maturation involves T cell receptor (TCR) recognition of major histocompatibility complex/self-antigen complexes. In this communication, we studied the ability of minor lymphocyte stimulating (Mls) determinants to act as self-tolerogens in the selection of the T cell repertoire. We demonstrate that unprimed T cells from normal as well as TCR transgenic mice form Mls-specific conjugates with antigen-presenting cells, and that this TCR-ligand interaction leads to elevation of intercellular Ca2+ ([Ca2+]i). Peripheral T cells from TCR transgenic mice expressing receptors specific for self-Mls antigen show no reactivities to Mlsa. However, a proportion of immature thymocytes from these mice show specific binding and strong [Ca2+]i elevation in response to self-antigen-presenting cells, although these thymocytes do not proliferate. This self-reactivity of thymocytes is inhibited by antibodies specific for TCR, CD4, CD8, class II molecules, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. These results demonstrate for the first time that before thymic negative selection, immature T cells can specifically interact with cells bearing self-antigen, and suggest that the resulting TCR-dependent signal transduction events provide a basis for negative selection of self-reactive T cells.

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