Mutation of the phospholipase C-γ1–binding site of LAT affects both positive and negative thymocyte selection

Sommers, Connie L.; Lee, Jan; Steiner, Kevin L.; Gurson, Jordan M.; DePersis, Corinne L.; El-Khoury, Dalal; Fuller, Claudette L.; Shores, Elizabeth W.; Love, Paul E.; Samelson, Lawrence E.

doi:10.1084/jem.20041869

Cited by 84 publications

(92 citation statements)

References 45 publications

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“…We expect, and prior experiments confirm, that both positive and negative selection are severely impaired in mice with this mutation (31). However peripheral T cells that do emerge participate in an uncontrolled lymphoproliferative syndrome (31). This could be due to altered signaling pathways or because TCRs with high affinity to endogenous pMHC that would normally be negatively selected are positively selected in mice with this mutation.…”

Section: Bimodal and Unimodal Signaling In Thymocytesmentioning

confidence: 63%

“…This also inhibits Ras activation by SOS because PLC␥1 is essential for forming complete LAT signalosomes, and the RasGRP pathway helps prime the SOS feedback loop (30). We expect, and prior experiments confirm, that both positive and negative selection are severely impaired in mice with this mutation (31). However peripheral T cells that do emerge participate in an uncontrolled lymphoproliferative syndrome (31).…”

Section: Bimodal and Unimodal Signaling In Thymocytesmentioning

confidence: 83%

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Origin of the sharp boundary that discriminates positive and negative selection of thymocytes

Prasad¹,

Zikherman

Das³

et al. 2009

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

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T lymphocytes play a key role in adaptive immunity and are activated by interactions of their T cell receptors (TCR) with peptides (p) derived from antigenic proteins bound to MHC gene products. The repertoire of T lymphocytes available in peripheral organs is tuned in the thymus. Immature T lymphocytes (thymocytes) interact with diverse endogenous peptides bound to MHC in the thymus. TCR expressed on thymocytes must bind weakly to endogenous pMHC (positive selection) but must not bind too strongly to them (negative selection) to emerge from the thymus. Negatively selecting pMHC ligands bind TCR with a binding affinity that exceeds a sharply defined (digital) threshold. In contrast, there is no sharp threshold separating positively selecting ligands from those that bind too weakly to elicit a response. We describe results of computer simulations and experiments, which suggest that the contrast between the characters of the positive and negative selection thresholds originates in differences in the way in which Ras proteins are activated by ligands of varying potency. The molecular mechanism suggested by our studies generates hypotheses for how genetic aberrations may dampen the digital negative selection response, with concomitant escape of autoimmune T lymphocytes from the thymus.positive feedback ͉ Ras activation ͉ signal transduction ͉ T cell antigen receptor ͉ thymic development

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Section: Bimodal and Unimodal Signaling In Thymocytesmentioning

confidence: 63%

Section: Bimodal and Unimodal Signaling In Thymocytesmentioning

confidence: 83%

Origin of the sharp boundary that discriminates positive and negative selection of thymocytes

Prasad¹,

Zikherman

Das³

et al. 2009

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

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“…In addition to the developmental block in LAT Y136F mice, thymocyte selection was profoundly affected (Sommers et al 2005) and Treg cells (Lu and Rudensky 2009) did not develop (Koonpaew et al 2006;Wang et al 2008). Abnormal cytokine production was observed in these mice, especially elevated levels of IL-4.…”

Section: In Vivo Functions Of Lat Phosphotyrosines and Cysteinesmentioning

confidence: 95%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

153

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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“…According to this hypothesis, potentially autoreactive T cells could then migrate to peripheral lymphoid organs and activate B cells, which would be expressing self peptide-MHC class II complexes to which the T cell repertoire had not been negatively selected. Using Lat Y136F mice expressing the HY TCR, an MHC class I-restricted TCR originally calibrated in a LAT-proficient context, it has been shown recently that the "window" for positive and negative selection has been shifted in LAT mutant mice (34). Therefore, it is likely that CD4 T cells developing in Lat Y136F mice are nevertheless appropriately selected in the context of the crippled LAT molecules (19).…”

Section: Polyclonal B Cell Activation By Lat Y136f T Cellsmentioning

confidence: 99%

The Th2 Lymphoproliferation Developing inLatY136FMutant Mice Triggers Polyclonal B Cell Activation and Systemic Autoimmunity

Genton

Wang

Izui

et al. 2006

The Journal of Immunology

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Lat Y136F knock-in mice harbor a point mutation in Tyr136 of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the LatY136F mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of LatY136F mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In LatY136F mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in LatY136F serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in LatY136F mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.

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Mutation of the phospholipase C-γ1–binding site of LAT affects both positive and negative thymocyte selection

Cited by 84 publications

References 45 publications

Origin of the sharp boundary that discriminates positive and negative selection of thymocytes

Origin of the sharp boundary that discriminates positive and negative selection of thymocytes

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

The Th2 Lymphoproliferation Developing inLatY136FMutant Mice Triggers Polyclonal B Cell Activation and Systemic Autoimmunity

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