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J Exp Med. 2016 Oct 17;213(11):2437-2457. Epub 2016 Sep 19.

The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells.

Author information

1
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France.
2
CRCM, Marseille Protéomique, Institut Paoli-Calmettes, Aix Marseille Université, INSERM, CNRS, 13009 Marseille, France.
3
Exbio Praha, Vestec, Czech Republic.
4
Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France.
5
School of Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, China.
6
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France bernardm@ciml.univ-mrs.fr malissen@ciml.univ-mrs.fr.

Abstract

The RLTPR cytosolic protein, also known as CARMIL2, is essential for CD28 co-stimulation in mice, but its importance in human T cells and mode of action remain elusive. Here, using affinity purification followed by mass spectrometry analysis, we showed that RLTPR acts as a scaffold, bridging CD28 to the CARD11/CARMA1 cytosolic adaptor and to the NF-κB signaling pathway, and identified proteins not found before within the CD28 signaling pathway. We further demonstrated that RLTPR is essential for CD28 co-stimulation in human T cells and that its noncanonical pleckstrin-homology domain, leucine-rich repeat domain, and proline-rich region were mandatory for that task. Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable for CD28 co-stimulation in both mouse and human. Our findings suggest that the scaffolding role of RLTPR predominates during CD28 co-stimulation and underpins the similar function of RLTPR in human and mouse T cells. Along that line, the lack of functional RLTPR molecules impeded the differentiation toward Th1 and Th17 fates of both human and mouse CD4+ T cells. RLTPR was also expressed in both human and mouse B cells. In the mouse, RLTPR did not play, however, any detectable role in BCR-mediated signaling and T cell-independent B cell responses.

PMID:
27647348
PMCID:
PMC5068240
DOI:
10.1084/jem.20160579
[Indexed for MEDLINE]
Free PMC Article

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