scholarly journals Thymus-independent positive and negative selection of T cells expressing a major histocompatibility complex class I restricted transgenic T cell receptor alpha/beta in the intestinal epithelium.

1993 ◽  
Vol 178 (6) ◽  
pp. 1947-1957 ◽  
Author(s):  
P Poussier ◽  
H S Teh ◽  
M Julius
Keyword(s):  
T Cell Receptor ◽  
Intestinal Epithelium ◽  
Transgenic Animals ◽  
Cell Receptor ◽  
Alpha Beta ◽  
High Level ◽  
Selection Of ◽  
Cell Receptor Alpha

We demonstrate that in the mouse intestinal epithelium the selection of T lymphocytes expressing a transgenic T cell receptor alpha/beta (TCR-alpha/beta) specific for male antigen (H-Y) in the context of H-2Db depends on the differential expression of H-Y and H-2Db in situ. In H-2Db transgenic males, there is no reduction in the number of intestinal intraepithelial lymphocytes (IEL), and the four main subsets of IEL expressing TCR-alpha/beta, defined by the differential expression of CD4, CD8 alpha, and CD8 beta, are present. Moreover, the level of expression of CD8 alpha and CD8 beta on CD8+ IEL subsets is unaltered. The frequency of CD8 alpha+ IEL expressing CD8 beta, in H-2Db male mice, however, is significantly decreased and these cells do not express the transgenic TCR. In contrast, virtually all CD8 alpha+beta- IEL in the same animals express the transgenic TCR. Still, these potentially autoreactive cells are refractile to H-Y/H-2Db stimulation in vitro. Both H-2Db and H-2Dd transgenic females contain high frequencies of cells expressing the transgenic TCR among CD8 alpha+beta- and CD8 alpha+beta+ IEL. However, two possibly related phenotypic features are peculiar to H-2Db female mice. The frequency of CD8 alpha+ IEL expressing CD8 beta is increased in these mice and, while in H-2Dd females the level of the transgenic TCR alpha chain expressed on CD8 alpha+beta+ IEL is uniformly low, some of the CD8 alpha+beta+ IEL in H-2Db females express a high level of both transgenic TCR chains. It is important to note, the ability of CD8 alpha+beta+ IEL to respond to H-Y/H-2Db stimulation in vitro is restricted to those coexpressing a high level of both transgenic TCR chains. The analysis of athymic radiation chimeras using adult thymectomized recipients of distinct H-Y/H-2 haplotypes, reconstituted with bone marrow from H-2Db transgenic females, demonstrates that all IEL subsets present in unmanipulated transgenic animals develop in the absence of a thymus. These IEL are phenotypically identical to those found in unmanipulated transgenic animals sharing the H-Y/H-2 haplotype of athymic recipients. Taken together, these results demonstrate that in the absence of male antigen, expression of H-2Db in the intestinal epithelium results in the positive selection of functional IEL specific for male antigen, in situ. When both H-Y and H-2Db are expressed in the intestinal epithelium, CD8 alpha+beta+ IEL expressing the transgenic TCR are negatively selected, while the frequency of nonfunctional CD8 alpha+beta- IEL expressing the transgenic CR is increased.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Thymus-independent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes.

1992 ◽  
Vol 176 (1) ◽  
pp. 187-199 ◽  
Author(s):  
P Poussier ◽  
P Edouard ◽  
C Lee ◽  
M Binnie ◽  
M Julius
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lamina Propria ◽  
T Cell Receptor ◽  
Intestinal Epithelium ◽  
Negative Selection ◽  
Cell Receptor ◽  
Normal Numbers ◽  
Alpha Beta ◽  
Selection Of

We demonstrate that mouse intestinal intraepithelial lymphocytes (IEL) can be divided into subsets based on the differential expression of functional T cell receptor alpha/beta (TCR-alpha/beta) signaling complexes. Two subsets, CD4+ 8 alpha + beta - and CD8 alpha + beta -, are refractory to stimulation with anti-TCR-alpha/beta and contain high frequencies of potentially self-reactive cells. In contrast, the CD4+ and CD8 alpha + beta + IEL subsets are responsive to anti-TCR-alpha/beta and depleted of potentially self-reactive cells. The analysis of fetal liver radiation chimeras using adult thymectomized recipients demonstrates that the four TCR-alpha/beta + IEL subsets are generated in normal numbers in the absence of the thymus. Moreover, expression of the major histocompatibility complex class II-encoded I-E molecule and Mls1a in the gut of the athymic host results in the negative selection of potentially self-reactive T cells expressing V beta 11 and V beta 6, respectively, from those IEL subsets that express functional TCR-alpha/beta signaling complexes. Neither the spleen nor the Peyer's patches of athymic recipients contain T cells of donor origin. In contrast, normal numbers of phenotypically and functionally mature CD4+ and CD8 alpha + beta + T cells of donor origin are found in the lamina propria of chimeric animals. The phenotypic analysis of lymphocytes obtained from Ly5 congenic parabionts reveals that peripheral T cells migrate rapidly to the Peyer's patches and lamina propria, but not to the intestinal epithelium. Taken together, these results demonstrate that the intestinal epithelium is a thymus-independent site of T lymphopoiesis, where selection of the T cell repertoire involves the deletion of potentially self-reactive cells in situ. Moreover, the appearance of donor-derived, phenotypically mature T cells, exclusively in the lamina propria of athymic radiation chimeras, suggests that mature IEL expressing functional TCR-alpha/beta migrate to this site.

Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells

Science ◽  
1992 ◽  
Vol 256 (5062) ◽  
pp. 1448-1452 ◽  
Author(s):  
K. Philpott ◽  
J. Viney ◽  
G Kay ◽  
S Rastan ◽  
E. Gardiner ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Lymphoid Development ◽  
Receptor Alpha ◽  
Alpha Beta ◽  
Cell Receptor Alpha

scholarly journals Evidence for in vivo clonal proliferation of unique population of blood CD4-/CD8- T cells bearing T-cell receptor alpha and beta chains in two normal men

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 2965-2972 ◽  
Author(s):  
Y Kusunoki ◽  
Y Hirai ◽  
S Kyoizumi ◽  
M Akiyama
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Nk Cell ◽  
Cell Receptor ◽  
Cell Markers ◽  
Clonal Proliferation ◽  
Alpha Beta

Abstract Rare T lymphocytes bearing CD3 surface antigen and T-cell receptor (TCR) alpha and beta chains, but lacking both CD4 and CD8 antigens, viz, TCR alpha beta+CD4–8- cells, appear at a frequency of 0.1% to 2% in peripheral blood TCR alpha beta+ cells of normal donors. Here we report two unusual cases, found among 100 healthy individuals studied, who showed an abnormally elevated frequency of these T cells, ie, 5% to 10% and 14% to 19%. Southern blot analyses of the TCR alpha beta+CD4–8- clones all showed the identical rearrangement patterns for each individual, demonstrating that these are derivatives of a single T cell. The same rearrangement patterns were also observed for the freshly isolated lymphocytes of TCR alpha beta+CD4-CD8- fraction, which excludes the possible bias in the processes of in vitro cloning. These TCR alpha beta+CD4–8- T cells were found to express other mature T-cell markers such as CD2, CD3, and CD5 antigens, as well as natural killer (NK) cell markers (CD11b, CD16, CD56, and CD57 antigens) for both individuals. Further, although lectin-dependent or redirected antibody- dependent cell-mediated cytotoxicities were observed for both freshly sorted lymphocytes of TCR alpha beta+CD4–8- fraction and in vitro established clones, NK-like activity was not detected.

scholarly journals CD4-CD8- T cell receptor alpha beta T cells: generation of an in vitro major histocompatibility complex class I specific cytotoxic T lymphocyte response and allogeneic tumor rejection.

1991 ◽  
Vol 174 (1) ◽  
pp. 193-201 ◽  
Author(s):  
M Mieno ◽  
R Suto ◽  
Y Obata ◽  
H Udono ◽  
T Takahashi ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
Cell Receptor ◽  
Tumor Rejection ◽  
Class I ◽  
Cd4 Cells ◽  
Spleen Cells ◽  
Cd8 Cells ◽  
Histocompatibility Complex ◽  
Alpha Beta

The generation of an in vitro major histocompatibility complex class I specific response of CD4-CD8- T cell receptor (TCR) alpha beta cytotoxic T lymphocytes (CTL) and their allogeneic tumor rejection were investigated. Inocula of BALBRL male 1 were rejected in C57BL/6 (B6) mice treated with minimum essential medium (MEM) (control), anti-L3T4 (CD4) monoclonal antibody (mAb) or anti-Lyt-2.2 (CD8) mAb and CTL against the tumor were generated in vitro. No rejection and no induction of CTL were observed in B6 mice treated with anti-L3T4 (CD4) plus anti-Lyt-2.2 (CD8) mAb. CTL with the classical Thy-1+ CD3+CD4-CD8+ TCR alpha beta phenotype were generated in mixed lymphocyte tumor cell culture (MLTC) spleen cells from B6 mice treated with MEM (control) or anti-L3T4 (CD4) mAb, whereas CTL with an unusual Thy-1+CD3+CD4-CD8- TCR alpha beta phenotype were generated in MLTC spleen cells from anti-Lyt-2.2 (CD8) mAb-treated B6 mice. Both types of CTL were reactive with both H-2Kd and Dd (Ld) class I antigen. These findings suggest that when CD4+ cells were blocked by anti-L3T4 (CD4) mAb, CD8+ CTL mediated rejection, and when CD8+ cells were blocked by anti-Lyt-2.2 (CD8) mAb, CD4+ cells were capable of mediating rejection, although less efficiently than CD8+ cells, by inducing CD4-CD8- TCR alpha beta CTL. The finding that adoptive transfer of CD4 and CD8-depleted MLTC spleen cells, obtained from anti-Lyt-2.2 (CD8) mAb-treated B6 mice that had rejected BALBRL male 1, resulted in rejection of BALBRL male 1 inoculated into B6 nu/nu mice confirmed the above notion. CTL clones with the CD4-CD8- TCR alpha beta phenotype specific for Ld were established.

scholarly journals Oligoclonal repertoire of the CD8 alpha alpha and the CD8 alpha beta TCR-alpha/beta murine intestinal intraepithelial T lymphocytes: evidence for the random emergence of T cells.

1994 ◽  
Vol 180 (4) ◽  
pp. 1345-1358 ◽  
Author(s):  
A Regnault ◽  
A Cumano ◽  
P Vassalli ◽  
D Guy-Grand ◽  
P Kourilsky
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Lymph Node ◽  
T Cell Receptor ◽  
Global Analysis ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Beta Chain ◽  
Alpha Beta ◽  
Cell Receptor Alpha

The epithelium of the small intestine in normal euthymic mice contains a large number of intraepithelial lymphocytes (IEL), some of which bear a T cell receptor alpha/beta (TCR-alpha/beta). About half of these TCR-alpha/beta IEL display the CD8 alpha alpha phenotype and the remaining have the CD8 alpha beta or the CD4 phenotypes. To examine whether TCR-alpha/beta IEL have a TCR-beta chain repertoire as diverse as that of TCR-alpha/beta lymph node lymphocytes (LNL), we used a recently described PCR technique that allows a global analysis of the TCR-beta chain repertoire. Within any given mouse, the repertoires expressed in both CD8 alpha alpha and CD8 alpha beta TCR-alpha/beta IEL populations are oligoclonal and nonoverlapping between the two subsets. The clones are largely conserved through the length of the small intestine of the same individual. However, genetically identical individuals raised under indistinguishable environmental conditions display distinct oligoclonal repertoires. Those findings indicate that few cells of CD8 alpha alpha or of the CD8 alpha beta phenotype are responsible for the repopulation of the intestinal epithelium.

scholarly journals The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides.

1990 ◽  
Vol 172 (1) ◽  
pp. 27-33 ◽  
Author(s):  
J S Danska ◽  
A M Livingstone ◽  
V Paragas ◽  
T Ishihara ◽  
C G Fathman
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Amino Acid Sequences ◽  
Antigenic Specificity ◽  
Antigenic Peptides ◽  
Surface Complexes ◽  
Receptor Alpha ◽  
Alpha Beta ◽  
Cell Receptor Alpha

The T cell receptor alpha/beta (TCR-alpha/beta) is encoded by variable (V), diversity (D), joining (J), and constant (C) segments assembled by recombination during thymocyte maturation to produce a heterodimer that imparts antigenic specificity to the T cell. Unlike immunoglobulins (Igs), which bind free antigen, the ligands of TCR-alpha/beta are cell surface complexes of intracellularly degraded antigens (i.e., peptides) bound to and presented by polymorphic products of the major histocompatibility complex (MHC). Therefore, antigen recognition by T cells is defined as MHC restricted. A model has been formulated based upon the similarity between TCR-alpha/beta V region and Ig Fab amino acid sequences, and the crystal structure of the MHC class I and Ig molecules. This model predicts that the complementarity determining regions (CDR) 1 and 2, composed of TCR V alpha and V beta segments, primarily contact residues of the MHC alpha helices, whereas V/J alpha and V/D/J beta junctional regions (the CDR3 equivalent) contact the peptide in the MHC binding groove. Because polymorphism in MHC proteins is limited relative to the enormous diversity of antigenic peptides, the TCR may have evolved to position the highly diverse junctional residues (CDR3), where they have maximal contact with antigen bound in the MHC peptide groove. Here, we demonstrate a definitive association between CDR3 sequences in both TCR alpha and beta chains, and differences in recognition of antigen fine specificity using a panel of I-Ed-restricted, myoglobin-reactive T cell clones. Acquisition of these data relied in part upon a modification of the polymerase chain reaction that uses a degenerate, consensus primer to amplify TCR alpha chains without foreknowledge of the V alpha segments they utilize.

scholarly journals Lymphocyte proliferation in mice congenitally deficient in T-cell receptor alpha beta + cells.

1994 ◽  
Vol 91 (25) ◽  
pp. 11948-11952 ◽  
Author(s):  
J. L. Viney ◽  
L. Dianda ◽  
S. J. Roberts ◽  
L. Wen ◽  
C. A. Mallick ◽  
...  
Keyword(s):  
T Cell ◽  
Beta Cells ◽  
T Cell Receptor ◽  
Lymphocyte Proliferation ◽  
Cell Receptor ◽  
Receptor Alpha ◽  
Alpha Beta ◽  
Cell Receptor Alpha
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