Inherited immunodeficiencies associated with proximal and distal defects in T cell receptor signaling and co-signaling

Latour, Sylvain

doi:10.1016/j.bj.2022.01.013

Cited by 6 publications

(7 citation statements)

References 106 publications

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“…Mutations in TCR signaling components are involved in causing immune dysregulation manifestations such as autoimmunity and inflammation. These defects are especially associated with susceptibility to pathogens like Epstein–Barr virus or Human Papilloma Virus which suggests a specialization of co-stimulatory molecules taking part in T cell responses to specific pathogens [ 27 ].…”

Section: Also In This Issuementioning

confidence: 99%

What makes tics tick? Insights into Tourette syndrome

Kattner¹

2022

Biomedical Journal

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Section: Also In This Issuementioning

confidence: 99%

What makes tics tick? Insights into Tourette syndrome

Kattner¹

2022

Biomedical Journal

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“…Monogenic variants in genes encoding for TCR signaling components result in inborn errors of immunity (IEI) with varying degrees of immunological impairment and a diverse spectrum of clinical phenotypes depending on the affected protein and the severity of the mutation [ 1 , 2 ]. The loss of CD3δ, -ε or -ζ results in almost absent T-cell development [ 3 ], presenting as severe combined immunodeficiency (SCID) characterized by a profound susceptibility to opportunistic infections, failure to thrive, and death within the first 2 years of life unless the patients undergo hematopoietic stem cell transplantation (HSCT) [ 4 ]. In contrast, patients with mutations in TCR signaling components as ZAP70 , ITK, SLP76 , or LAT may have even normal numbers of peripheral T cells with yet altered function [ 5 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…These combined immunodeficiencies (CID) are defined by increased susceptibility to opportunistic infections and carry a high incidence of morbidity and mortality. CID are also frequently associated with autoimmunity and other forms of immune dysregulation [ 1 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK

Keller,

Kfir-Erenfeld,

Matusewicz

et al. 2023

J Clin Immunol

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Mutations affecting T-cell receptor (TCR) signaling typically cause combined immunodeficiency (CID) due to varying degrees of disturbed T-cell homeostasis and differentiation. Here, we describe two cousins with CID due to a novel nonsense mutation in LCK and investigate the effect of this novel nonsense mutation on TCR signaling, T-cell function, and differentiation. Patients underwent clinical, genetic, and immunological investigations. The effect was addressed in primary cells and LCK-deficient T-cell lines after expression of mutated LCK. Results Both patients primarily presented with infections in early infancy. The LCK mutation led to reduced expression of a truncated LCK protein lacking a substantial part of the kinase domain and two critical regulatory tyrosine residues. T cells were oligoclonal, and especially naïve CD4 and CD8 T-cell counts were reduced, but regulatory and memory including circulating follicular helper T cells were less severely affected. A diagnostic hallmark of this immunodeficiency is the reduced surface expression of CD4. Despite severely impaired TCR signaling mTOR activation was partially preserved in patients’ T cells. LCK-deficient T-cell lines reconstituted with mutant LCK corroborated partially preserved signaling. Despite detectable differentiation of memory and effector T cells, their function was severely disturbed. NK cell cytotoxicity was unaffected. Residual TCR signaling in LCK deficiency allows for reduced, but detectable T-cell differentiation, while T-cell function is severely disturbed. Our findings expand the previous report on one single patient on the central role of LCK in human T-cell development and function. Graphical Abstract

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“…Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of na€ ıve T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of T EMRA .…”

Section: Introductionmentioning

confidence: 99%

Inborn errors of immunity underlying defective T-cell memory

Boutboul,

Picard,

Latour

2023

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review T-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations. Recent findings This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-κB) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-κB, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit. Summary Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.

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Inherited immunodeficiencies associated with proximal and distal defects in T cell receptor signaling and co-signaling

Cited by 6 publications

References 106 publications

What makes tics tick? Insights into Tourette syndrome

What makes tics tick? Insights into Tourette syndrome

Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK

Inborn errors of immunity underlying defective T-cell memory

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