Functional requirement of tyrosine residue 429 within CD5 cytoplasmic domain for regulation of T cell activation and survival

Mier‐Aguilar, Carlos A.; Vega-Baray, Benjamín; Burgueño‐Bucio, Erica; Lozano, Francisco; García‐Zepeda, Eduardo A.; Raman, Chander; Soldevila, Gloria

doi:10.1016/j.bbrc.2015.09.033

Cited by 8 publications

(9 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibitory signaling ability of CD5 has been linked to its cytoplasmic tail and more specifically to tyrosines embedded in the proximal region of the membrane [50] or the pseudoimmunoreceptor tyrosine-based motif [51,52]. Such a negative immunomodulatory ability positions CD5 as a putative "immune checkpoint regulator" in a similar way to that reported for cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), among others, whose blockade has open up new pathways for cancer immunotherapy [53].…”

Section: Cd5: a Negative Modulator Of Immune Responsesmentioning

confidence: 99%

“…Furthermore, the CD5 receptor has also been described to contribute to cell survival through association of its C-terminal cytoplasmic region with the serine/threonine kinase CK2 [47,48]. Thus, the CD5-dependent CK2 activation would deliver anti-apoptotic signals likely involved in homeostatic T-and B1a-cell survival and eventually resistance to activation-induced cell death (AICD) [49].The inhibitory signaling ability of CD5 has been linked to its cytoplasmic tail and more specifically to tyrosines embedded in the proximal region of the membrane [50] or the pseudoimmunoreceptor tyrosine-based motif [51,52]. Such a negative immunomodulatory ability positions CD5 as a putative "immune checkpoint regulator" in a similar way to that reported for cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), among others, whose blockade has open up new pathways for cancer immunotherapy [53].…”

mentioning

confidence: 99%

“…1A, [61]). This was attributed to differential FasL expression regulation by CD5, since CD5 low cells expressed higher levels of FasL and consequently presented higher caspase-8 activity, though the contribution of CD5-dependent CK2 pro-survival activity [49,52] should also be taken into consideration [62]. Indeed, CD5 knock-out mice exhibited slow tumor growth coupled to increased T-cell activation marker expression (e.g., CD25 and CD69) by TILs (Fig.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

et al. 2017

Self Cite

View full text Add to dashboard Cite

Scavenger receptors (SRs) are structurally heterogeneous cell surface receptors characterized by their capacity to remove extraneous or modified self-macromolecules from circulation, thus avoiding the accumulation of noxious agents in the extracellular space. This scavenging activity makes SRs important molecules for host defense and homeostasis. In turn, SRs keep the activation of the steady-state immune response in check, and participate as co-receptors in the priming of the effector immune responses when the macromolecules are associated with a threat that might compromise host homeostasis. Therefore, SRs built up sophisticated sensor mechanisms controlling the immune system, which may be exploited to develop novel drugs for cancer immunotherapy. In this review, we focus on the regulation of the anti-tumor immune response by two paradigmatic SRs: the lymphocyte receptor CD5 and the more broadly distributed scavenger receptor class B type 1 (SR-B1). Cancer immunity can be boosted by blockade of SRs working as immune checkpoint inhibitors (CD5) and/or by proper engagement of SRs working as innate danger receptor (SR-B1). Thus, these receptors illustrate both the complexity of targeting SRs in cancer immunotherapy and also the opportunities offered by such an approach. Keywords:Cancer immunotherapy r CD5 r Danger signal r Immune-checkpoint r Scavenger receptor r Scavenger receptor class B type 1 r Toll-like receptors IntroductionThe cancer-immunity cycle can be subverted by tumors at many steps, thus novel therapeutic interventions should be considered for all these possibilities [1]. This cycle starts with the release of tumor antigens and their subsequent capture by professional antigen-presenting cells (mainly, dendritic cells; DCs) for the activation of effector cells of the innate and adaptive immune Correspondence: Dr. Pedro Berraondo e-mail: pberraondol@unav.es system. This is a highly regulated process aimed at maintaining the integrity of the host without inducing significant side effects (e.g., inflammation or autoimmunity) [2]. Tissue homeostasis involves phagocytic processes to remove the excess of native or modified molecules from unviable or stressed cells, as well as from invading microbial agents [3]. Such molecules include lipids, whose intracellular levels should be carefully controlled to sustain proper cell metabolism; endogenous glyco-and lipo-proteins, damaged or * These authors contributed equally to this work. * * These authors are senior co-authors of this work. [4,5]. This phagocytic activity should be coupled to an alarm signal system that awakens other effector mechanisms of the immune system when the tissue damage cannot be controlled by the removal of the endogenous or exogenous molecules. To this end, the immune system has a myriad of specialized soluble or membrane-bound receptors called pattern recognition receptors (PRRs). These PRRs are non-polymorphic, nonclonally distributed, and germ-line encoded receptors recognizing microorganism-associated molecular patterns (MAMPs) -tha...

show abstract

Section: Cd5: a Negative Modulator Of Immune Responsesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, the lack of CD5-CK2 signaling had no effect on expression of CD5 on any thymic subpopulation Thus, TCR-induced CD5 upregulation is likely to be regulated by other CD5 cytoplasmic regions, like the CD5-ITIM domain [7]. The elevated basal pERK observed in adult mice led us to predict that nTreg numbers would be expanded in CD5-ΔCK2BD thymus, as we previously showed in CD5 -/- mice [9].…”

Section: Discussionmentioning

confidence: 83%

“…Several signaling domains within the cytoplasmic tail of CD5 have been proposed to mediate its role as negative regulator of TCR signaling. Among them, an (ITIM)-like motif (pseudo-ITIM) comprising tyrosines 429–441 [7], as well as the carboxy-terminal region containing Y463 [8]. …”

Section: Introductionmentioning

confidence: 99%

CD5-CK2 Signaling Modulates Erk Activation and Thymocyte Survival

et al. 2016

Self Cite

View full text Add to dashboard Cite

CD5 is well recognized for its importance in thymic selection. Although this property of CD5 has been attributed to its ITIM-domain dependent regulation of TCR-signal strength, the mechanism has not been established. A second major signaling domain within the cytoplasmic tail of CD5 is a CK2 binding/activation domain (CD5-CK2BD). Using a gene-targeted mouse in which the CD5-CK2BD is selectively ablated (CD5-ΔCK2BD), we determined that loss of function of CD5-CK2 signaling in a MHC-II selecting TCR transgenic (OT-II) mouse resulted in decrease in double positive (DP) thymocytes, which correlated with enhanced apoptosis. Remarkably, DP cells expressing high levels of CD5 and CD69 and single positive (CD4+SP) thymocytes were increased in CD5-ΔCK2BD mice indicating that CD5-CK2 signaling regulates positive selection and promotes survival. Consistent with this possibility, we determined that the activation and nuclear localization of ERK as well as apoptosis was greater in thymic populations from OTII CD5-ΔCK2BD mice than OTII CD5-WT mice following injection of OVA323-339-peptide. The mobilization of Ca2+, an early event of TCR activation, was not altered by the loss of CD5-CK2 signaling. Collectively, these data demonstrate that the CD5-CK2 signaling axis regulates positive selection by modulating activation of ERK and promoting survival independent of proximal TCR signals.

show abstract

The multiple faces of CD5

Burgueño‐Bucio

Mier‐Aguilar

Soldevila

2019

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

Since its discovery, over 30 years ago, CD5 has been used as a marker to identify T cells, B1‐a cells, and B cell chronic lymphocytic leukemia cells. Throughout the years, many studies have described the functional relevance of CD5 as a modulator of T and B cell receptor signaling. However, it has not been until recent years that CD5 has emerged as a functional receptor in other areas of the immune system. Here, we review some of the most important aspects of CD5 as a modulator of TCR and BCR signaling, cell survival receptor both in T and B cells during health and disease, as well as the newly discovered roles of this receptor in thymocyte selection, T cell effector differentiation, and immune tolerance. CD5 was found to promote T cell survival by protecting autoreactive T cell from activation‐induced cell death, to promote de novo induction of regulatory T cells in the periphery, to modulate Th17 and Th2 differentiation, and to modulate immune responses by modulating dendritic cell functions. CD5 is overexpressed in Tregs and Bregs, which are fundamental to maintain immune homeostasis. The newly established roles of CD5 in modulating different aspects of immune responses identify this receptor as an immune checkpoint modulator, and therefore it could be used as a target for immune intervention in different pathologies such as cancer, autoimmune diseases or infections.

show abstract

Functional requirement of tyrosine residue 429 within CD5 cytoplasmic domain for regulation of T cell activation and survival

Cited by 8 publications

References 34 publications

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

CD5-CK2 Signaling Modulates Erk Activation and Thymocyte Survival

The multiple faces of CD5

Contact Info

Product

Resources

About