The Differential Regulation of Lck Kinase Phosphorylation Sites by CD45 Is Critical for T Cell Receptor Signaling Responses

McNeill, Louise; Salmond, Robert J.; Cooper, Joanne C.; Carret, Céline; Cassady-Cain, Robin L.; Roche-Molina, Marta; Tandon, Panna; Holmes, Nick D.; Alexander, Denis R.

doi:10.1016/j.immuni.2007.07.015

Cited by 165 publications

(211 citation statements)

References 52 publications

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“…1 C and D). This is consistent with our previous findings in allelic series thymocytes as well as independent reports with other transgenic lines (29,30).…”

Section: Resultssupporting

confidence: 94%

“…We and others have shown that CD45 plays a negative regulatory role as well as a positive regulatory role during TCR signaling by dephosphorylating the activation loop as well as the inhibitory tyrosine of Lck (29,30). Whether an analogous negative regulatory role exists in B cells is unclear, however (31).…”

mentioning

confidence: 97%

“…Unexpectedly, studies of mice with subphysiological expression of CD45 single isoforms demonstrated that low levels of CD45 were sufficient to rescue T-cell development, but not to normalize B-cell maturation (27)(28)(29). We and others have shown that CD45 plays a negative regulatory role as well as a positive regulatory role during TCR signaling by dephosphorylating the activation loop as well as the inhibitory tyrosine of Lck (29,30).…”

mentioning

confidence: 99%

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Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Zikherman

Doan

Parameswaran

et al. 2011

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

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The receptor-like tyrosine phosphatase CD45 positively regulates antigen receptor signaling by dephosphorylating the inhibitory tyrosine of the src family kinases. CD45-deficient mice fail to fully unmask the role of CD45 in B cells because of the expression of a partially redundant tyrosine phosphatase, CD148. However, mice that are doubly deficient in CD45 and CD148 exhibit a very early block in B-cell development, thereby obscuring later roles for CD45. To overcome these limitations, here we take advantage of an allelic series of mice in which CD45 expression is titrated broadly (0-180%). Although high expression of CD45 inhibits T-cell receptor (TCR) signaling, we show that CD45 plays a purely positive regulatory role during B-cell receptor (BCR) signaling. In concert with exaggerated BCR signaling, increasing CD45 expression drives enhanced receptor editing in the bone marrow and profound loss of follicular and marginal zone B cells in the spleen. In the context of the IgHEL/sHEL model of B-cell tolerance, such high CD45 expression transforms anergy into deletion. Unexpectedly, elimination of the autoantigen sHEL in this model system in order to block clonal deletion fails to rescue survival of mature B cells. Rather, high CD45 expression reduces B-cell activating factor receptor (BAFFR) expression and inhibits B-cell activating factor (BAFF)-induced B-cell survival in a cell-intrinsic manner. Taken together, our findings reveal how CD45 function diverges in T cells and B cells, as well as how autoreactive B cells are censored as they transit development.antigen receptor signaling | Lyn

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“…1 C and D). This is consistent with our previous findings in allelic series thymocytes as well as independent reports with other transgenic lines (29,30).…”

Section: Resultssupporting

confidence: 94%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Zikherman

Doan

Parameswaran

et al. 2011

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

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“…2B). As reported (19,20), phosphorylation of the C-terminal and autocatalytic tyrosines was increased in KO thymocytes. Surprisingly, there was a modest increase in phosphorylation of the C-terminal tyrosine and a more marked increase in phosphorylation of the autocatalytic tyrosine in WEDGE thymocytes.…”

Section: Resultssupporting

confidence: 85%

“…Below this threshold, only the positive effects of CD45 phosphatase activity may be appreciated. This reasoning may explain why even very low levels of a CD45 transgene reconstitute thymic development in CD45 null mice (20). However, these studies did not evaluate the T cell repertoire at a qualitative level.…”

Section: Discussionmentioning

confidence: 99%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

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

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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T‐Cell Antigen Recognition – Lessons from the Past and Projections into the Future

Platzer

Huppa

2020

Encyclopedia of Life Sciences

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T‐cells are central to adaptive immunity and arguably to this date the most intensely studied cells in life sciences. Paying tribute to their developmental plasticity and the complexities associated with many of their physiological functions, numerous aspects of their physiology are still far from being understood to an extent that would be sufficient to rationally design therapies effectively targeting allergies, autoimmunity and cancer. T‐cell antigen recognition is no exception: this field took up speed with the rise of monoclonal antibodies and the first successful cloning of the T‐cell antigen receptor (TCR) genes roughly 40 years ago. In the meantime, hundreds of TCRs have been crystallised in complex with their nominal peptide/MHC (pMHC) binding partners and many TCR‐pMHC interaction kinetics have been measured. Furthermore most, if not all signalling molecules acting downstream of the TCR have been identified. Despite these accomplishments, we are still searching for convincing explanations as to how T‐cells mange to reliably detect the presence of even a single antigen on the surface of antigen‐presenting cells (APCs). Elaborating underlying mechanisms will invariably require a more advanced understanding of the molecular, subcellular and cellular context in which T‐cell antigen recognition operates. What renders this endeavour both challenging and exciting is the rather weak strength and promiscuous nature of TCR‐pMHC binding and the fact that antigenic pMHCs are typically vastly outnumbered on APC surfaces by structurally similar, yet nonstimulatory pMHCs. While research of the last 20 years has provided some clarity, it has also caused at times controversies, which need to be resolved to unleash the full potential that T‐cells offer for clinical progress. Key Concepts T‐cells are indispensable for orchestrating and executing cellular and humoral adaptive immune responses; in recurrent communication with other cells of the immune system, T‐cells continuously patrol our body in search for antigenic peptide fragments derived from pathogens or cancer‐derived neoantigens. T‐cells are exquisitely sensitive for their nominal antigen as they can detect the presence of even a single stimulatory pMHC amongst thousands of structurally similar yet nonstimulatory pMHCs on the very crowded surface of an APC. Despite considerable progress in the field over the last 40 years, the molecular, biophysical and (sub‐) cellular principles underlying the detection efficiency associated with T‐cell antigen recognition and are far from being resolved. Given the complexities inherent to processes associated with T‐cell antigen recognition, which involve (1) the short‐lived nature of key protein–protein and protein–lipid interactions and (2) mechanical forces acting within the narrow confines of the immunological synapse, we consider integrative approaches combining classical biochemistry, structural biology and genetics with biophysics, advanced live‐cell imaging and systems biology most likely to provide much‐needed answers to most fundamental questions. Easy access to both experimental/analysis modalities and primary data of published work as well as improved literacy in the areas of biophysics and systems biology will help accelerate progress in the field of T‐cell antigen recognition with immediate and far‐reaching clinical implications benefiting allergy, autoimmune and cancer patients.

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The Differential Regulation of Lck Kinase Phosphorylation Sites by CD45 Is Critical for T Cell Receptor Signaling Responses

Cited by 165 publications

References 52 publications

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

T‐Cell Antigen Recognition – Lessons from the Past and Projections into the Future

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