Positive and Negative Selection of T Cells

Starr, Timothy K.; Jameson, Stephen C.; Hogquist, Kristin A.

doi:10.1146/annurev.immunol.21.120601.141107

Cited by 1,347 publications

(746 citation statements)

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“…Although the precise mechanisms underlying the development of CD4 versus CD8 lineage T cells are still controversial, interactions among TCRs, coreceptors, and self-pMHC are critical for the outcome (4,5,7). Recent studies suggest that the duration of TCR signaling may control CD4 versus CD8 lineage differentiation (47).…”

Section: Discussionmentioning

confidence: 99%

“…The concordance of CD4 or CD8 lineage development with specificity for class I or II MHC is established during differentiation of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes in the thymus by a process referred to as positive selection (4). Whether a DP thymocyte differentiates into a CD4 ϩ or CD8 ϩ T cell depends on differences in TCR signaling as a result of interactions among TCR, coreceptors, and self-peptide-MHC (self-pMHC) complexes (5)(6)(7)(8).…”

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confidence: 99%

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Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Holler

Mahajan

et al. 2006

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

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Most ␣␤ T cells belong to one of the two lineages defined by the mutually exclusive expression of CD8 or CD4 coreceptors, which bind MHC class I and class II molecules, respectively. Because the binding of the coreceptors to MHC molecules stabilizes weak interactions between TCRs and peptide-MHC (pMHC) complexes, CD8 ϩ T cells are MHC class I-restricted whereas CD4 ϩ T cells are MHC class II-restricted. The concordance of CD4 or CD8 lineage development with specificity for class I or II MHC is established during differentiation of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes in the thymus by a process referred to as positive selection (4). Whether a DP thymocyte differentiates into a CD4 ϩ or CD8 ϩ T cell depends on differences in TCR signaling as a result of interactions among TCR, coreceptors, and self-peptide-MHC (self-pMHC) complexes (5-8).Many TCRs are known to interact not only with self-but also with foreign MHC molecules (alloreactivity). Among the bestdocumented examples is the recognition of different pMHC complexes by a TCR called 2C (9). The 2C TCR was derived from a CD8 ϩ cytotoxic T lymphocyte (CTL) clone from an H-2 b mouse (BALB.B) that was injected with H-2 d cells (10, 11). The 2C TCR reacts with L d in association with two overlapping peptides QL-SPFPFDL (QL9) and p2Ca derived from ␣-ketoglutarate dehydrogenase (10,12,13). The 2C TCR is also alloreactive to K bm3 in association with the dEV8 peptide derived from NADHubiquinone oxoreductase (14,15). By constructing transgenic mice expressing the 2C TCR and crossing the TCR transgene onto different H-2 backgrounds, it was shown that the positive selecting MHC for the 2C T cells is K b (16,17). Among the naturally derived peptides recognized by the 2C TCR in association with L d and K bm3 , p2Ca and dEV8 bind weakly to K b and behave as weak agonists (18). However, several strong agonist peptides have been identified in combinatorial libraries to associate with K b and activate the 2C T cells (19). Among them, SIYRYYGL (SIY) has been extensively characterized. In addition to recognizing various peptides in association with MHC class I L d , K bm3 , and K b molecules, the 2C TCR was also shown recently to recognize a nonclassical class I molecule, leading to differentiation of CD8 ϩ T cells that home to the intestine during fetal and neonatal development (20).The ability of a given TCR to interact with multiple MHC molecules, especially both class I and class II, can have a significant influence on the development of CD4 versus CD8 T cells. For example, the HY TCR nominally recognizes class I D b for CD8 T cell development but also interacts with class II I-A b for CD4 T cell development (21). Similarly, the HA and AND TCRs nominally interact with class II MHC for CD4 T cell development but also promote the development of CD8 T cells on either the RAG Ϫ/Ϫ or the CD4 Ϫ/Ϫ plus TCR␣ Ϫ/Ϫ background (22, 23). The development of CD8 HA or AND transgenic T cells was shown to require the interaction of the TCRs with both class I and class II MHC molecules....

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Holler

Mahajan

et al. 2006

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

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“…Instead, we found a specific defect in the activation of extracellular signal-regulated kinase (Erk), a critical mediator of positive selection (1). This result identifies Itpkb as a unique link between the TCR and the Ras mitogen-activated protein kinase (MAPK) pathway, which is essential for T cell development.…”

mentioning

confidence: 85%

“…Lymphoid precursors destined to become T cells arrive in the thymus from the bone marrow, where they face a gauntlet of checkpoints to determine their ultimate fate (reviewed in ref. 1). Briefly, T cell development in the thymus can be followed by the expression of the two T cell receptor (TCR) coreceptors CD4 and CD8.…”

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Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity

Wen

Pletcher

Warashina

et al. 2004

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

146

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The Role of Regulatory T Lymphocytes in Amyotrophic Lateral Sclerosis

2018

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Positive and Negative Selection of T Cells

Cited by 1,347 publications

References 238 publications

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity

The Role of Regulatory T Lymphocytes in Amyotrophic Lateral Sclerosis

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Positive and Negative Selection of T Cells

Cited by 1,347 publications

References 238 publications

Development of CD4+T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Development of CD4+T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity

The Role of Regulatory T Lymphocytes in Amyotrophic Lateral Sclerosis

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Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms