Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells

Horková, Veronika; Drobek, Ales; Mueller, Daniel L.; Gubser, Céline; Niederlová, Veronika; Wyss, Lena; King, Catrina E.; Zehn, Dietmar; Štěpánek, Ondřej

doi:10.1016/j.celrep.2020.01.008

Cited by 29 publications

(39 citation statements)

References 59 publications

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“…Approximately 34% of CD4 coreceptors were bound with Lck in naïve CD4 + T cells, and ∼4.6% of CD8αβ coreceptors were bound with Lck in naïve CD8 + T cells ( SI Appendix , Fig. S6 D ), which agreed with a recent report ( 25 ). This significantly higher Lck coupling for CD4 coreceptors than CD8 coreceptors may be due to the higher binding affinity between Lck and CD4 compared to Lck and CD8 ( 9 , 26 ).…”

Section: Resultssupporting

confidence: 92%

“…However, the higher amount of Lck sequestration in CD4 T cells may lead to a slower but more steady response of CD4 T cells after infection, supporting CD8 T cells and other immune cells by secreting cytokines. Recently, lymph node T cells of CD8.4 (CD8 coreceptor with a CD4 cytoplasmic tail) transgenic mice were found to have less self-reactivity compared to WT mice (25). This may due to the lower amount of free Lck that exists in the CD8.4 cells, as more Lck is bound by the CD8.4 in these T cells.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction of Lck with CD4 and CD8 is essential to ensure that DP cells do not respond to non-MHC activation of TCR during thymic selection and is therefore critical for selecting the MHC-restricted αβTCR repertoire ( 31 , 32 ). Recently, Lck and coreceptor coupling was shown to be higher in peripheral T cells compared to DP thymocytes ( 25 ). Although the percentage of Lck-bound coreceptors increases from DP to peripheral T cells, a fraction of Lck always exists that is unbound by the coreceptors.…”

Section: Discussionmentioning

confidence: 99%

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Lck bound to coreceptor is less active than free Lck

Wei

Brzostek

Sankaran

et al. 2020

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

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Src family kinase Lck plays critical roles during T cell development and activation, as it phosphorylates the TCR/CD3 complex to initiate TCR signaling. Lck is present either in coreceptor-bound or coreceptor-unbound (free) forms, and we here present evidence that the two pools of Lck have different molecular properties. We discovered that the free Lck fraction exhibited higher mobility than CD8α-bound Lck in OT-I T hybridoma cells. The free Lck pool showed more activating Y394 phosphorylation than the coreceptor-bound Lck pool. Consistent with this, free Lck also had higher kinase activity, and free Lck mediated higher T cell activation as compared to coreceptor-bound Lck. Furthermore, the coreceptor-Lck coupling was independent of TCR activation. These findings give insights into the initiation of TCR signaling, suggesting that changes in coreceptor-Lck coupling constitute a mechanism for regulation of T cell sensitivity.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Lck bound to coreceptor is less active than free Lck

Wei

Brzostek

Sankaran

et al. 2020

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

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“…However, several recent studies are beginning to cast doubt on the assumption that coreceptors are wholly occupied by Lck. In 2016 and 2020, two groups reported unexpectedly small occupancy values using the co-IP method: 6% (Parrish et al, 2016) and 37% (Horkova et al, 2020) for the CD4-Lck interaction in single-positive T cells. Even lower values were reported for CD8 + T cells and double-positive thymocytes (Horkova et al, 2020).…”

Section: Lck and Coreceptor Occupancymentioning

confidence: 99%

Coreceptors and TCR Signaling – the Strong and the Weak of It

Mørch

Bálint

Santos

et al. 2020

Front. Cell Dev. Biol.

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The T-cell coreceptors CD4 and CD8 have well-characterized and essential roles in thymic development, but how they contribute to immune responses in the periphery is unclear. Coreceptors strengthen T-cell responses by many orders of magnitudebeyond a million-fold according to some estimates-but the mechanisms underlying these effects are still debated. T-cell receptor (TCR) triggering is initiated by the binding of the TCR to peptide-loaded major histocompatibility complex (pMHC) molecules on the surfaces of other cells. CD4 and CD8 are the only T-cell proteins that bind to the same pMHC ligand as the TCR, and can directly associate with the TCRphosphorylating kinase Lck. At least three mechanisms have been proposed to explain how coreceptors so profoundly amplify TCR signaling: (1) the Lck recruitment model and (2) the pseudodimer model, both invoked to explain receptor triggering per se, and (3) two-step coreceptor recruitment to partially triggered TCRs leading to signal amplification. More recently it has been suggested that, in addition to initiating or augmenting TCR signaling, coreceptors effect antigen discrimination. But how can any of this be reconciled with TCR signaling occurring in the absence of CD4 or CD8, and with their interactions with pMHC being among the weakest specific protein-protein interactions ever described? Here, we review each theory of coreceptor function in light of the latest structural, biochemical, and functional data. We conclude that the oldest ideas are probably still the best, i.e., that their weak binding to MHC proteins and efficient association with Lck allow coreceptors to amplify weak incipient triggering of the TCR, without comprising TCR specificity.

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“…[8][9][10][11] Indeed, it is the cytotoxic CD8 + T cell population, rather than the predominantly regulatory CD4 + T cell population, that is most responsive to near-self antigens. 12 The technology has been improved by the employment of checkpoint inhibitors for 'immune checkpoint blockade' 13 and depletion of patients' existing in vivo T cell populations (lympho-depletive regimes) 14 prior to infusion of their own T cells, 15 which may have been engineered to match tumour antigens. 16,17 While tumour infiltrating lymphocytes have long been studied in this context, 8 peripheral blood mononuclear cells (PBMC) are proving a better T cell source since they are at a developmental stage less prone to metabolic 'exhaustion', an antigen dose-dependent tolerogenic process that is likely in tumour microenvironments.…”

mentioning

confidence: 99%

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

Forsdyke

2020

Scand J Immunol

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After prolonged extracorporeal multiplication in physiological culture media, there can be curative infusions of a cancer patient's own cytotoxic T cells (adoptive T cell transfer; ACT), which must achieve efficient activation in potentially adverse tumour microenvironments. With spectacular, yet irregular, success, improvements are needed. Developing lymphoid cells are biologically selected, not only for ‘near‐self’ reactivity (positive selection), but also to avoid self‐reactivity (negative selection). Thus, success requires harnessing near‐self cells while avoiding extreme autoimmune phenomena. Abrupt metabolic changes accompanying T cell activation to leave the G0 stage and enter the G1 stage of the cell cycle (eg enhanced glycolysis) are accompanied by increased transcription of the G0S9 gene that mediates salvage synthesis of NAD+ from nicotinamide; the latter has recently been shown to increase the efficiency of ACT. Despite theoretical and experimental advances, there has not been parallel progress in simulating in vivo conditions with culture media that were initially formulated for their positive benefits for tumour cell lines (cell survival and proliferation). Yet for lymphoid cells, inhibition or death (ie immunological tolerance) is as important as their activation and proliferation (immunological response). Thus, use of media optimized for the latter may mask the former. The resilience of established culture protocols may have been partly politically driven. However, unphysiological conditions have sometimes yielded fortuitous insights. Optimization of culture media for specific tissues must consider the nature of problems addressed in research settings and the need to avoid mishaps in clinical settings.

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Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells

Cited by 29 publications

References 59 publications

Lck bound to coreceptor is less active than free Lck

Lck bound to coreceptor is less active than free Lck

Coreceptors and TCR Signaling – the Strong and the Weak of It

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

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