MHC Restriction: Where Are We Now?

Zareie, Pirooz; Farenc, Carine; Gruta, Nicole L. La

doi:10.1089/vim.2019.0195

Cited by 7 publications

(6 citation statements)

References 101 publications

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“…An alternate model suggests that TCR recognition of pMHC is driven during thymic selection by the need for the CD4 or CD8 coreceptors to bind MHC and deliver coreceptor-associated Lck to the CD3 signaling complex (5). Because of the proposed positioning of CD3 in the TCR-pMHC-CD4/CD8 complex, this model posits that only canonical polarity TCR-pMHC interactions are conducive to signaling (6)(7)(8). The biological significance of the canonical docking polarity remains unclear and has not been tested experimentally because of the rarity of TCR-pMHC docking polarities outside of this paradigm (1,(9)(10)(11).…”

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confidence: 99%

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Zareie

Szeto

Farenc

et al. 2021

Science

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T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRβ-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db–NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.

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confidence: 99%

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Zareie

Szeto

Farenc

et al. 2021

Science

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“…HLA class II–restricted naive CD4 + T cells are selected by a very stringent and complex process in the thymus where the avidity and duration of MHC-TCR interactions are fundamental ( Glassman et al, 2018 ; La Gruta et al, 2018 ; Singer, 2002 ; Van Laethem et al, 2022 ; Zareie et al, 2020 ). Remarkably, Singer and colleagues recently reported a new FlipFlop mouse model where the Cd4 and Cd8α gene loci encode the opposite co-receptor protein ( Shinzawa et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Helper T cell immunity in humans with inherited CD4 deficiency

Guérin,

Moncada-Vélez,

Jackson

et al. 2024

Journal of Experimental Medicine

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CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5–61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple’s disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4−CD8− T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4−CD8− αβ T cells exhibit intact responses to HLA class II–restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

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“…In support of the innate-like nature of MAIT cells’ TCRs is the fact that they recognize the monomorphic MR1 in complex with a limited number of metabolite antigens [ 7 , 14 ]. In contrast, the classical MHC-I proteins are highly polymorphic and the peptides they bind are diverse, depending on the flexibility of the TCR V region, which is often sufficient to allow the TCR to interact with numerous MHC-I/peptide complexes [ 58 ].…”

Section: Tcr Antigens Of Mait Versus Mr1t Cellsmentioning

confidence: 99%

MR1-Restricted T Cells in Cancer Immunotherapy

Flores-Villanueva

Sobhani

Wang

et al. 2020

Cancers

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Major histocompatibility complex class I-related (MR1) was first identified as a cell membrane protein involved in the development and expansion of a unique set of T cells expressing an invariant T-cell receptor (TCR) α-chain. These cells were initially discovered in mucosal tissues, such as the intestinal mucosa, so they are called mucosal-associated invariant T (MAIT) cells. MR1 senses the presence of intermediate metabolites of riboflavin and folic acid synthesis that have been chemically modified by the side-products of glycolysis, glyoxal or methylglyoxal. These modified metabolites form complexes with MR1 and translocate from the endoplasmic reticulum to the plasma membrane where MAIT cells’ TCRs recognize them. Recent publications report that atypical MR1-restricted cytotoxic T cells, differing from MAIT cells in TCR usage, antigen, and transcription factor profile, recognize an as yet unknown cancer-specific metabolite presented by MR1 in cancer cells. This metabolite may represent another class of neoantigens, beyond the neo-peptides arising from altered tumor proteins. In an MR1-dependent manner, these MR1-restricted T cells, while sparing noncancerous cells, kill many cancer cell lines and attenuate cell-line-derived and patient-derived xenograft tumors. As MR1 is monomorphic and expressed in a wide range of cancer tissues, these findings raise the possibility of universal pan-cancer immunotherapies that are dependent on cancer metabolites.

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MHC Restriction: Where Are We Now?

Cited by 7 publications

References 101 publications

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Helper T cell immunity in humans with inherited CD4 deficiency

MR1-Restricted T Cells in Cancer Immunotherapy

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