A non-conserved amino acid variant regulates differential signalling between human and mouse CD28

Porciello, Nicla; Grazioli, Paola; Campese, Antonio Francesco; Kunkl, Martina; Caristi, Silvana; Mastrogiovanni, Marta; Muscolini, Michela; Spadaro, Francesca; Favre, C.; Nunès, Jacques A.; Borroto, Aldo; Alarcón, Balbino; Screpanti, Isabella; Tuosto, Loretta

doi:10.1038/s41467-018-03385-8

Cited by 26 publications

(44 citation statements)

References 54 publications

(113 reference statements)

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“…Others evidenced a pivotal role of TGFβ in combination with IL-6, IL-1β IL-23, or IL-21 for inducing the expression of RORγτ and Th17 cell differentiation [88][89][90]. In human, but not in mouse [91], CD28, an important co-stimulatory molecule expressed on T cells [92,93] and involved in the regulation of both tolerance and autoimmunity [94], has been also described to stimulate CD4 + T cells to produce inflammatory cytokines and chemokines related to the Th17 cell phenotype [95,96] and to enhance the inflammatory response in MS by reprogramming T cell metabolism and favoring the expression of Th17-associated cytokines [97,98].…”

Section: Th17 Cellsmentioning

confidence: 99%

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

Kunkl

Frascolla

Amormino

et al. 2020

Cells

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175

107

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Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.

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Section: Th17 Cellsmentioning

confidence: 99%

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

Kunkl

Frascolla

Amormino

et al. 2020

Cells

Self Cite

175

107

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“…CD28 has a pivotal role in the orchestration of the immune response that makes it a precious target for the treatment of immune-based diseases, but caution is needed to translate experimental results from mice to humans because differences in CD28 functions and signaling capability might determine dramatic effects. For instance, our recent identification of a single amino acid variant within the cytoplasmic tail of human and rodent CD28 (P 212 in human versus A 210 in rodent) as a critical residue for human CD28 pro-inflammatory and signaling functions 58 raises the question of whether or not rodents can be used as a model for the study of CD28-mediated functions and for the safety of new therapeutic approaches. Thus, new efforts to develop better in vivo and in vitro systems are required to take advantage of the great potential retained in the co-stimulatory pathway and to provide novel insights into CD28 biology and implications for therapies.…”

Section: Discussionmentioning

confidence: 99%

CD28 between tolerance and autoimmunity: the side effects of animal models

Porciello

Kunkl²,

Tuosto³

2018

F1000Res

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Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans.

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“…higher proliferation (Frauwirth et al 2002). Finally, minor differences in the amino acid sequences of human and mouse CD28 may be responsible for differential signaling effects: cytokine induction versus association with cytoskeletal proteins (Porciello et al 2018). .…”

Section: Structural and Signaling Aspects Of Cd28mentioning

confidence: 99%

T cell costimulation, checkpoint inhibitors and anti-tumor therapy

et al. 2020

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The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on naïve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.

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A non-conserved amino acid variant regulates differential signalling between human and mouse CD28

Cited by 26 publications

References 54 publications

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis

CD28 between tolerance and autoimmunity: the side effects of animal models

T cell costimulation, checkpoint inhibitors and anti-tumor therapy

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