The generation of mature T cells requires interaction of the αβ T-cell receptor with major histocompatibility antigens

Scott, Bernadette; Blüthmann, Horst; Teh, Hung Sia; Boehmer, Harald von

doi:10.1038/338591a0

Cited by 211 publications

(102 citation statements)

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“…Upon production of a functional TCR-c i polypeptide chain, a complete TCRcio-CD3 complex becomes expressed on the cell surface in low concentration. At this stagerepertoire selection takes place, resulting in the production of mature CD4+ and CD8+ single positive (SP)t T cells with high TCR-cio-CD3 expression (9,10).…”

Section: Duringembryogenesis T Lineage Committed Lymphoidmentioning

confidence: 99%

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Levelt

Carsetti

Eichmann

1993

The Journal of Experimental Medicine

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SummaryRecent studies have shown that maturation of CD4-8 -double negative (DN) thymocytes to the CD4+8+ double positive (DP) stage is dependent on expression of the T cell receptor (TCR)-a polypeptide. The exact mechanism by which the TCR-0 chain regulates this maturation step remains unknown. Previous experiments had suggested that in the presence of some TCR+ thymocytes, additional DN thymocytes not expressing a TCR-0 chain may be recruited to mature to the DP stage. The recent demonstration of an immature TCR-0-CD3 complex on early thymocytes lead to the alternative hypothesis that signal transduction through an immature TCR-CD3 complex may induce maturation to the DP stage. In the latter case, maturation to the DP stage would depend on the expression of TCR-0-CD3 in the same cell. We examined these two hypotheses by studying the expression of the intra-and extracellular CD3e, CD3', and TCR-0 polypeptides in intrathymic subpopulations during embryogenesis. CD3e and CD3' were expressed intracellularly 2 and 1 d, respectively, before intracellular expression ofthe TCR-0 chain, potentially allowing immediate surface expression ofan immature TCR-(-CD3 complex as soon as functional rearrangement of a TCR-0 gene locus has been accomplished. Calcium mobilization could be induced by stimulation with anti-CD3e mAb as soon as intracellular TCR-0 was detectable, suggesting that a functional TCR-0-CD3 complex is indeed expressed on the surface of early thymocytes. From day 17 on, most cells were in the DP stage, and over 95% of the DP cells expressed on the TCR-0 chain intracellularly. At day 19 of gestation, extremely low concentrations of TCR-a chain and CD3E were detectable on the cell surface of nearly all thymocytes previously thought to be TCR-CD3 negative. These findings strongly support the hypothesis that maturation to the DP stage depends on surface expression of and subsequent signal transduction through an immature TCR-( .CD3 complex and suggest that maturation to the DP stage by recruitment, if it occurs at all, is of minor relevance. Duringembryogenesis, T lineage committed lymphoidprecursor cells home to the thymus, where they undergo a developmental program, marked by sequential surface expression ofvarious stage specific glycoproteins and rearrangement of the TCR gene loci . One ofthe early thymocyte markers is Pgp-1, a molecule that may play a role in homing of precursor cells to the thymus. Further maturation ofthymocytes results in the expression ofthe ci chain ofthe interleukin-2 receptor (IL-2R) and downregulation of Pgp-1 (for review see 1, 2). The IL-2Ra+ stage coincides with a wave of V > D rearrangements of the TCR-0 locus (3). An important control point in intrathymic development is the subsequent transition into the CD4+8+ stage, accompanied by a burst ofcell divisions, loss ofIL-2Ra expression, and arrest of rearrangement, i.e., allelic exclusion, of the TCR-0 gene locus (4-7). During the DP stage, rearrangement of the TCR-a locus takes place (for review see 8). Upon production of a function...

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Section: Duringembryogenesis T Lineage Committed Lymphoidmentioning

confidence: 99%

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Levelt

Carsetti

Eichmann

1993

The Journal of Experimental Medicine

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“…T lymphocytes are positively or negatively selected in the thymus as a result of interactions between their T cell receptors (TCR) and thymic peptide-major histocompatibility complexes (MHC) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Much of the recent work on thymic selection was influenced by experiments that examined T cell responses to peptide analogs, produced from the antigenic peptide by substitution of amino acid residues involved in interaction with the TCR.…”

mentioning

confidence: 99%

Interactions with multiple peptide ligands determine the fate of developing thymocytes

Williams¹,

Tarazona²,

Wack³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Thymocytes are positively or negatively selected depending on interactions between their T cell receptors (TCR) and peptides presented by major histocompatibility complex molecules. We have previously shown that apoptosis of thymocytes from an ␣␤ TCR-transgenic mouse (F5), induced by antigenic peptide, can be inhibited specifically by an antagonist peptide variant in an in vitro culture model. We have now extended these experiments by demonstrating that the antagonist peptide can inhibit natural negative selection of maturing thymocytes, induced by endogenously expressed antigen, in fetal thymic organ cultures (FTOC). This inhibition resulted in the rescue and maturation of thymocytes that would otherwise have been deleted. Mature T cells generated in these cultures were able to respond to antigen by producing limited quantities of interferon-␥, but unlike T cells from control FTOC, they required exogenous interleukin-2 to generate cytolytic effector cells. Interestingly, the antagonist peptide also accelerated the development of F5 thymocytes in the absence of the negatively selecting ligand. These data suggest that the developmental fate of a thymocyte may be determined by the recognition of multiple distinct peptide ligands during thymic selection. Alterations in the profiles of selecting peptides presented in the thymus would thus have profound effects on the size and autoreactive potential of the T cell repertoire generated.T lymphocytes are positively or negatively selected in the thymus as a result of interactions between their T cell receptors (TCR) and thymic peptide-major histocompatibility complexes (MHC) (1-11). Much of the recent work on thymic selection was influenced by experiments that examined T cell responses to peptide analogs, produced from the antigenic peptide by substitution of amino acid residues involved in interaction with the TCR. Such peptide analogs can generate qualitatively different T cell responses compared with those produced by the antigenic peptide (12). In particular, some analogs were shown to act as TCR antagonists and inhibit T cell responses to the antigenic peptide (13). Several studies have shown that antagonist peptides are capable of positively selecting (9, 10), negatively selecting (14, 15), or blocking positive selection (16) of thymocytes. However, other studies have found that the ability of a peptide to select thymocytes positively or negatively does not always correlate with its properties as a TCR antagonist (10,11,17,18).We have previously reported an analog peptide (19) that was capable of inhibiting antigen-specific lysis of target cells by cytotoxic T lymphocyte (CTL) from ␣␤ TCR (F5)-transgenic mice (20,21). Furthermore, this peptide was shown to inhibit apoptosis of transgenic thymocytes (19) in an in vitro suspension culture assay (22). Because the suspension culture could not support the development of immature thymocytes, we could not determine whether this inhibition would result in the rescue and complete maturation of thymocytes. In the pre...

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“…In addition, within the thymus, positive selection favors the emergence of a highly diverse T cell repertoire and ensures the quality control of TCRs, while negative selection eliminates self-reactive thymocytes (5,6). Both processes involve specific interactions with self-MHC molecules (7)(8)(9)(10).…”

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confidence: 99%

Size Estimate of the αβ TCR Repertoire of Naive Mouse Splenocytes

Casrouge

Beaudoing

Dalle

et al. 2000

The Journal of Immunology

285

236

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The diversity of the T cell repertoire of mature T splenocytes is generated, in the thymus, by pairing of α and β variable domains of the αβ TCR and by the rearrangements of various gene segments encoding these domains. In the periphery, it results from competition between various T cell subpopulations including recent thymic migrants and long-lived T cells. Quantitative data on the actual size of the T cell repertoire are lacking. Using PCR methods and extensive sequencing, we have measured for the first time the size of the TCR-αβ repertoire of naive mouse T splenocytes. There are 5–8 × 105 different nucleotide sequences of BV chains in the whole spleen of young adult mice. We have also determined the size of the BV repertoire in a subpopulation of AV2+ T splenocytes, which allows us to provide a minimum estimate of the αβ repertoire. We find that the mouse spleen harbors about 2 × 106 clones of about 10 cells each. This figure, although orders of magnitude smaller than the maximum theoretical diversity (estimated up to 1015), is still large enough to maintain a high functional diversity.

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The generation of mature T cells requires interaction of the αβ T-cell receptor with major histocompatibility antigens

Cited by 211 publications

References 7 publications

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Interactions with multiple peptide ligands determine the fate of developing thymocytes

Size Estimate of the αβ TCR Repertoire of Naive Mouse Splenocytes

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