Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells

Horková, Veronika; Drobek, Ales; Paprčková, Darina; Niederlová, Veronika; Prasai, Avishek; Uleri, Valeria; Kraller, Markus; Cesnekova, Michaela; Janusova, Sarka; Salyova, Eva; Tsyklauri, Oksana; Kadlecek, Theresa A.; Křížová, Kateřina; Platzer, René; Schober, Kilian; Busch, Dirk H.; Weiss, Arthur; Huppa, Johannes B.; Štěpánek, Ondřej

doi:10.1038/s41590-022-01366-0

Cited by 21 publications

(34 citation statements)

References 59 publications

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“…It is critical for transducing cell membrane signals that activate intracellular signaling cascades. 16,[64][65][66] Lck has been reported to be associated with the co-receptors CD4 and CD8 in T cells. 64 However, TCR signaling can also occur in the absence of CD4 or CD8 co-receptor involvement, likely by engaging membrane-bound Lck, not linked to CD4/CD8.…”

Section: An "Aberrant" Tcr Signalosome May Lead To Increased Il-5 Pro...mentioning

confidence: 99%

“…LAT is an adaptor protein whose tyrosine phosphorylation is critical for transmitting the TCR signal. 16,65,66 In common TCRpeptide-HLA interactions, CD4 or CD8 engagement brings LAT closer to protein tyrosine kinase ZAP 70, which phosphorylates LAT. 17,66 The resulting "LAT signalosome" links the TCR to primary with massive eosinophilia in mice.…”

Section: An "Aberrant" Tcr Signalosome May Lead To Increased Il-5 Pro...mentioning

confidence: 99%

“…LAT phosphorylation increases T-cell sensitivity to weak ligand stimuli (CD8) or affects cytokines (CD4). 16,17,65,66 (B) hypothetical IL-5-TCR signalosome model: in certain p-i stimulations, the TCR-drug/peptide/HLA interactions are affine enough to bypass CD4 engagement. Instead of Lck bound to CD4 coreceptors, membrane-bound Lck promotes the phosphorylation of ITAMs and activation of ZAP70.…”

Section: Summary and Con Clus Ionmentioning

confidence: 99%

“…Phosphorylation of ZAP70 by CD4/CD8‐Lck leads to its activation, which in turn phosphorylates LAT at five key tyrosine residues. LAT phosphorylation increases T‐cell sensitivity to weak ligand stimuli (CD8) or affects cytokines (CD4) 16,17,65,66 . (B) hypothetical IL‐5‐TCR signalosome model: in certain p‐i stimulations, the TCR‐drug/peptide/HLA interactions are affine enough to bypass CD4 engagement.…”

Section: Eosinophilia Due To P‐i Stimulationmentioning

confidence: 99%

“…The first is the lymphocyte‐specific protein tyrosine kinase (Lck), an Src kinase family member. It is critical for transducing cell membrane signals that activate intracellular signaling cascades 16,64–66 . Lck has been reported to be associated with the co‐receptors CD4 and CD8 in T cells 64 .…”

Section: Eosinophilia Due To P‐i Stimulationmentioning

confidence: 99%

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Drug hypersensitivity and eosinophilia: The decisive role of p‐i stimulation

Pichler

Thoo

Yerly

2023

Allergy

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Eosinophilia is a common finding in drug hypersensitivity reactions (DHR). Its cause is unclear, as neither antigen/allergen‐driven inflammation nor clonal expansion is involved. Most delayed‐DHRs are due to p‐i (pharmacologic interaction of drugs with immune receptors). These are off‐target activities of drugs with immune receptors that result in various types of T‐cell stimulation, some of which involve excessive IL‐5 production. Functional and phenotypic studies of T‐cell clones and their TCR‐transfected hybridoma cell lines revealed that some p‐i‐induced drug stimulations occur without CD4/ CD8 co‐receptor engagement. The CD4/CD8 co‐receptors link Lck (lymphocyte‐specific protein tyrosine kinase) and LAT (linker for activation of T cells) to the TCR. Alteration of Lck or LAT can result in a TCR signalosome with enhanced IL‐5 production. Thus, if a more affine TCR‐[drug/peptide/HLA] interaction allows bypassing the CD4 co‐receptor, a modified Lck/LAT activation may lead to a TCR signalosome with elevated IL‐5 production. This “IL‐5‐TCR‐signalosome” hypothesis could also explain eosinophilia in superantigen or allo‐stimulation (graft‐versus‐host disease), in which evasion of CD4/CD8 co‐receptors has also been described. It may open new therapeutic possibilities in certain eosinophilic diseases by directly targeting the IL‐5‐TCR signalosome.

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Section: An "Aberrant" Tcr Signalosome May Lead To Increased Il-5 Pro...mentioning

confidence: 99%

Section: An "Aberrant" Tcr Signalosome May Lead To Increased Il-5 Pro...mentioning

confidence: 99%

Section: Summary and Con Clus Ionmentioning

confidence: 99%

Section: Eosinophilia Due To P‐i Stimulationmentioning

confidence: 99%

Section: Eosinophilia Due To P‐i Stimulationmentioning

confidence: 99%

See 3 more Smart Citations

Drug hypersensitivity and eosinophilia: The decisive role of p‐i stimulation

Pichler

Thoo

Yerly

2023

Allergy

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Czech Young Immunologists: Bound by science, united in purpose

Vancikova,

Benešová,

Černý

et al. 2023

Eur J Immunol

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A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature

Lanz,

Erdem,

Ozcan

et al. 2023

J Clin Immunol

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Lymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αβT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency.

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Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells

Cited by 21 publications

References 59 publications

Drug hypersensitivity and eosinophilia: The decisive role of p‐i stimulation

Drug hypersensitivity and eosinophilia: The decisive role of p‐i stimulation

Czech Young Immunologists: Bound by science, united in purpose

A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature

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