The Role of Adaptor Proteins in the Biology of Natural Killer T (NKT) Cells

Abstract

Adaptor proteins contribute to the selection, differentiation and activation of natural killer T (NKT) cells, an innate(-like) lymphocyte population endowed with powerful immunomodulatory properties. Distinct from conventional T lymphocytes NKT cells preferentially home to the liver, undergo a thymic maturation and differentiation process and recognize glycolipid antigens presented by the MHC class I-like molecule CD1d on antigen presenting cells. NKT cells express a semi-invariant T cell receptor (TCR), which combines the Vα14-Jα18 chain with a Vβ2, Vβ7, or Vβ8 chain in mice and the Vα24 chain with the Vβ11 chain in humans. The avidity of interactions between their TCR, the presented glycolipid antigen and CD1d govern the selection and differentiation of NKT cells. Compared to TCR ligation on conventional T cells engagement of the NKT cell TCR delivers substantially stronger signals, which trigger the unique NKT cell developmental program. Furthermore, NKT cells express a panoply of primarily inhibitory NK cell receptors (NKRs) that control their self-reactivity and avoid autoimmune activation. Adaptor proteins influence NKT cell biology through the integration of TCR, NKR and/or SLAM (signaling lymphocyte-activation molecule) receptor signals or the variation of CD1d-restricted antigen presentation. TCR and NKR ligation engage the SH2 domain-containing leukocyte protein of 76kDa slp-76 whereas the SLAM associated protein SAP serves as adaptor for the SLAM receptor family. Indeed, the selection and differentiation of NKT cells selectively requires co-stimulation via SLAM receptors. Furthermore, SAP deficiency causes X-linked lymphoproliferative disease with multiple immune defects including a lack of circulating NKT cells. While a deletion of slp-76 leads to a complete loss of all peripheral T cell populations, mutations in the SH2 domain of slp-76 selectively affect NKT cell biology. Furthermore, adaptor proteins influence the expression and trafficking of CD1d in antigen presenting cells and subsequently selection and activation of NKT cells. Adaptor protein complex 3 (AP-3), for example, is required for the efficient presentation of glycolipid antigens which require internalization and processing. Thus, our review will focus on the complex contribution of adaptor proteins to the delivery of TCR, NKR and SLAM receptor signals in the unique biology of NKT cells and CD1d-restricted antigen presentation.

T cell receptor (TCR) signaling in health and disease

“…Adaptors are proteins that usually lack intrinsic enzymatic activity and instead possess multiple binding domains for phosphotyrosine, proline-rich region and lipid interactions, and sequence motifs that in turn are involved in binding to such domains. 11 , 12 The phosphorylated tyrosine residues on various adaptor proteins serve as binding sites for many critical effector enzymes and other adaptor proteins. 6 Thus, they behave as scaffolds, facilitating protein–protein interactions that aid in forming multiprotein complexes, thereby integrating signaling cascades necessary for efficient T cell biology.…”

Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T Cell Adaptor Gads

“…Whereas both Itk and SAP are required to promote the development of CD4 SP NKT thymocytes [15,16,63,64], NKT development was not perturbed in the absence of Gads.…”

On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity

“…In mammalian and plant cells, adaptor protein-3 homologs have been shown to be involved in both clathrin-dependent and independent vesicle formation for organelles such as lysosomes, as well as protein cargo sorting in relation to the endoplasmic reticulum and the Golgi apparatus (63)(64)(65). The digestive vacuole is analogous to a lysosome, and indeed other adaptor proteins have been identified in the haemoglobin digestion pathway, with AP-3 a notable omission (66).…”