Recognition of a Specific Self-Peptide: Self-MHC Class II Complex Is Critical for Positive Selection of Thymocytes Expressing the D10 TCR

Dao, Tao; Blander, J. Magarian; Sant’Angelo, Derek B.

doi:10.4049/jimmunol.170.1.48

Cited by 11 publications

(14 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both D10 and L51S mice were bred onto a C␣ Ϫ/Ϫ background to ensure that no endogenous ␣-chains were used for pairing with the transgenic ␤-chain. In separate, but related, studies we now show that this mutation in the TCR that lowers its affinity to its specific MHC:peptide ligand reduces positive selection of immature T cells in the thymus (42) and results in the appearance of mature memory phenotype CD4 T cells in the periphery. In this study we show that the memory phenotype of these CD4 T cells does not translate into effector memory function.…”

mentioning

confidence: 73%

See 1 more Smart Citation

A Pool of Central Memory-Like CD4 T Cells Contains Effector Memory Precursors

Blander

Sant’Angelo

Metz

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The L51S mutation in the D10.G4.1 TCR α-chain reduces the affinity of the TCR to its ligand by affecting the interactions among the TCR, the β-chain of I-Ak, and the bound peptide. We show that this mutation drives the generation of a pool of memory CD44highCD62LnegCD45RBneg CD4 TCR transgenic T cells. Their activation threshold is low, such that they proliferate in response to lower concentrations of agonist peptides than naive L51S CD4 T cells. Unlike effector memory CD4 T cells, however, they lack immediate effector function in response to TCR stimulation. These cells express IL-2Rα only after culture with specific peptide. Although they can be recovered from lymph nodes, the majority lack the expression of the lymph node homing receptor CCR7. When these cells receive a second TCR stimulation in vitro, they differentiate into potent Th2-like effector cells, producing high levels of IL-4 at doses of agonist peptide too low to stimulate cytokine release from similarly differentiated naive L51S CD4 T cells. Having these properties, the L51S TCR transgenic memory CD4 T cells cannot be classified as either strict central memory or effector memory, but, rather, as a pool of memory T cells containing effector memory precursors.

show abstract

mentioning

confidence: 73%

“…1C). This reduced number of CD4 T cells in the periphery is due to poor positive selection in the thymus (42).…”

Section: An Amino Acid Substitution From L To S At Position 51 Of Thementioning

confidence: 99%

A Pool of Central Memory-Like CD4 T Cells Contains Effector Memory Precursors

Blander

Sant’Angelo

Metz

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our model, we found that thymocytes exposed to IL-12-plus-IL-18 produce IFN-␥ that in turn can mediate IA-IE expression in cortical and medullary TEC. This is important considering that MHC class II expression by TEC is essential during negative and positive selection (37,38).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effect of IL-2, IL-12, and IL-18 on Thymocyte Apoptosis and Th1/Th2 Cytokine Expression

Rodríguez-Galán

Bream

Farr

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

In the periphery, IL-18 synergistically induces the expression of the Th1 cytokine IFN-γ in the presence of IL-12 and the Th2 cytokines IL-5 and IL-13 in the presence of IL-2. Although the expression of these cytokines has been described in the thymus, their role in thymic development and function remains uncertain. We report here that freshly isolated thymocytes from C57BL/6 and BALB/c mice stimulated in vitro with IL-2-plus-IL-18 or IL-12-plus-IL-18 produce large amounts of IFN-γ and IL-13. Analysis of the thymic subsets, CD4−CD8− (DN), CD4+CD8+, CD4+CD8−, and CD4−CD8+ revealed that IL-18 in combination with IL-2 or IL-12 induces IFN-γ and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-γ+ cells than cells in the later stage of maturation. Additionally, IL-18 in combination with IL-2 induces CCR4 (Th2-associated) and CCR5 (Th1-associated) gene expression. In contrast, IL-18-plus-IL-12 specifically induced CCR5 expression. The IL-2-plus-IL-18 or IL-12-plus-IL-18 effect on IFN-γ and IL-13 expression is dependent on Stat4 and NF-κB but independent of Stat6, T-bet, or NFAT. Furthermore, IL-12-plus-IL-18 induces significant thymocyte apoptosis when expressed in vivo or in vitro, and this effect is exacerbated in the absence of IFN-γ. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN-γ-dependent manner. Thus, the combination of IL-2, IL-12, and IL-18 can induce phenotypic and functional changes in thymocytes that may alter migration, differentiation, and cell death of immature T cells inside the thymus and potentially affect the Th1/Th2 bias in peripheral immune compartments.

show abstract

“…cDNA clones for wild-type HLA-DMA and the mutant version of HLA-DMB were cloned into the pMCFR expression vector (21). The vectors were transfected by electro- poration into the B cell line CH27 (22). Stable clones were derived by selection with G418.…”

Section: Methodsmentioning

confidence: 99%

Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

Kim

Guo

Sant’Angelo

2005

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

View full text Add to dashboard Cite

The specificity for self-MHC that is necessary for T cell function is a consequence of intrathymic selection during which T cell antigen receptors (TCRs) expressed by immature thymocytes are tested for their affinity for self-peptide:self-MHC. The germ-line-encoded segments of the TCR, however, are believed to have an innate specificity for structural features of MHC molecules. We directly tested this hypothesis by generating a transgenic mouse system in which the protein HLA-DM is expressed at the surface of thymic cortical epithelial cells in the absence of classical MHC molecules. The specialized intracellular function of HLA-DM has removed this MHC class II-like protein from the evolutionary forces that have been hypothesized to shape TCR-MHC interactions. Our study shows that a structural mimic of MHC class II is not sufficient to appropriately interact with the TCRs expressed by developing thymocytes. This result emphasizes the unique complementarity of TCR-MHC interactions that are maintained by the evolutionary pressures dictated by positive selection.T cell receptor ͉ thymocytes ͉ mice ͉ T lymphocytes ͉ thymus D evelopment of thymocytes is a multistep process that shapes the repertoire of mature T cells. Ideally, the mature T cell antigen receptor (TCR) repertoire is depleted of specificities that are overtly self-reactive, but is also diversified enough to mount effective immune responses (1, 2). Selection is based on the interactions of the TCRs expressed by immature CD4 ϩ CD8 ϩ , double-positive (DP) thymocytes with selfpeptide:self-MHC expressed on the surface of thymic stromal cells. Poorly defined criteria determine whether this receptorligand interaction is of sufficient avidity to drive development of DP thymocytes to mature single-positive, MHC class I-or MHC class II-restricted T cells.Unresolved issues regarding the positive selection of T cells include the extent that specific interactions of the TCR with MHC-bound self-peptides rather than interactions with MHC itself shape the mature CD4 ϩ T cell repertoire. This question has been addressed by a number of systems that have not produced concordant results (3-7). Such contradictory data have led to speculation that different TCRs may have different requirements for recognition of MHC-bound self-peptide. The inherent MHC reactivity of the preselection TCR repertoire is a second issue that has not been definitively answered. In other words, it is not clear whether the germ line-encoded regions of the TCR are predisposed toward interactions with MHC, or, alternatively, whether the ability of TCRs expressed by mature T cells to interact with MHC is fully a consequence of positive selection.Mutagenesis studies have suggested that the TCR has a conserved orientation of interaction with MHC molecules, and, therefore, conserved interactions between MHC molecules and TCRs seemed likely. Crystallographic studies of TCRs bound to MHC, however, have not fully confirmed this prediction (7). In retrospect, perhaps this finding is not surprising, consideri...

show abstract

Recognition of a Specific Self-Peptide: Self-MHC Class II Complex Is Critical for Positive Selection of Thymocytes Expressing the D10 TCR

Cited by 11 publications

References 52 publications

A Pool of Central Memory-Like CD4 T Cells Contains Effector Memory Precursors

A Pool of Central Memory-Like CD4 T Cells Contains Effector Memory Precursors

Synergistic Effect of IL-2, IL-12, and IL-18 on Thymocyte Apoptosis and Th1/Th2 Cytokine Expression

Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

Contact Info

Product

Resources

About