Background/Purpose:

Invariant Natural Killer T (iNKT) cells are a unique population of lymphocytes that express an invariant TCR alpha chain, and react to lipid antigens presented by non classical MHC class I like molecule CD1d. There is highly homologous population in human. iNKT cells carry out innate-like responses and produce large amount of diverse cytokines, including IFNgamma, IL-4, IL-17 and IL-21. Therefore, iNKT cells are involved in numerous inflammatory and pathological conditions, including rheumatic diseases such as SLE and RA.

iNKT cells are autoreactive, and it is not clear how their autoreactivity is regulated. This is an important question, especially relevant for understanding the pathogenesis of many human autoimmune diseases. Our discoveries, therefore, will potentially identify novel drug targets for the treatment of patients with SLE, RA and other autoimmune diseases in which abnormal activation of iNKT cells is observed.

Methods:

We use primary iNKT cell line as a model system to study iNKT cell autoreactivity. Microarray and RNA-seq were carried out to identify new regulators of iNKT autoreactivity.

Results:

We have found that the short-term cultured iNKT cells have greatly increased sensitivity to CD1d-lipid complexes derived from multiple sources. APCs that express a tail-deleted form of CD1d are defective to stimulate the iNKT cell lines in vitro. iNKT cell lines distinguish previously identified self lipid Ags from their structural homologs. Transfer experiments revealed that CD1d in the periphery down regulates the autoreactivity. However, tail-deleted CD1d is unable to completely control the reactivity of iNKT cells. RNAseq identified several candidate genes that may act down stream of CD1d-TCR interaction to regulate the function of iNKT cells, one of which is PTPN6/SHP1. The development of iNKT cells is impaired in the conditional knockout mice of SHP1, thus it prevents us from directly evaluating the role of SHP1 in the pheripheral iNKT cells. However, we observed several T cell exhaustion markers, such as PD-1 and FR4, express at higher level in SHP1 deficient iNKT cells. It is consistent with our hypothesis that SHP1 acts downstream of TCR and controls the reactivity of iNKT cells.

Conclusion:

We have designed a new a reliable system that demonstrates iNKT cell autoreactivity for CD1d in bulk populations with diverse TCR beta chains, rather than requiring a single hybridoma. iNKT cell autoreactivity is modulated by CD1d in the periphery and depends on the endolysosomal localization of CD1d. Gene expression profiling reveals new regulators of iNKT cell reactivity, for example, SHP1/PTPN6.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd1d-regulates-inkt-cell-autoreactivity/