NKT cell subsets in infection and inflammation
Introduction
NKT cells are a subset of lymphocytes that are characterised by the co-expression of the NK cell receptor, CD161, and a single large invariant TCR α chain (Vα24JαQ in the human and Vα14Jα28 in the mouse). Unlike conventional T cells, they recognise glycolipid antigens such as α-galactoceramide presented by the non-polymorphic class 1B molecule, CD1d [1], [2] and produce high levels of both IFN-γ and IL-4 on activation [3]. However, NKT cells are phenotypically and functionally heterogeneous. The different subsets of cells that are encompassed within the NKT population is not entirely clear. We have recently demonstrated on the basis of their IFN-γ and IL-4 secretion profile, that Type 1 and Type 2 lymphocytes, including NKT cells, are distinguishable by their specific cell surface markers, IL-18R and ST2L, respectively [4].
By directing the T cell immune response toward either a Th1 or Th2 response, NKT cells appear to regulate the development of certain autoimmune conditions. This is evident in patients with myasthenia gravis where a significant increase of Vα24 NKT cells occurs with a marked production of IFN-γ and IL-4 [5]. NKT cells are also prominent in three models of immune inflammation in the lung, with the OVA-asthma model showing an increase in IL-4 containing NKT cells whilst NKT cells synthesizing IFN-γ were prominent in the inflammatory or Th1-initiated fibrotic animal models. In contrast, patients with multiple sclerosis [6], scleroderma and Type 1 diabetes [7] show reduced numbers of Vα24-JαQ T cells. Similarly, in nonobese diabetic (NOD) mice and in systemic lupus prone (NZB/NZW) mice, NKT cells are deficient [8], [9], [10]. Furthermore, transfer of NKT cells or over-expression of Vα14-Jα28 cells could partially protect against disease in NOD mice [11], [12]. Thus, studies in both humans and rodents have demonstrated that NKT cells have a central role in the regulation of autoimmunity and induction of tolerance although the mechanism of action is unclear.
In addition to cytokine production and immune regulation, NKT cells have effector functions. When activated or IL-12 induced, they display potent cytolytic activities on tumour targets mediated by perforin/granzyme B [13], [14] and on Fas+ targets including double positive thymocytes via Fas ligand (FasL) expression [15]. They may also contribute to defence against viruses [16], [17]. Thus, NKT cells are pleotropic in their functions. However, the normal range of NKT cell numbers in human peripheral blood is not known. In addition, the association of NKT cell numbers and function with defined disease states remains to be determined. Here, we summarise recent work from our own laboratories showing the distribution of Type 1 and 2 NKT cells in patients with long term non-progressive HIV infection. We also report the distribution of NKT1 and NKT2 cells in two human chronic inflammatory diseases: within aortic wall lesions of patients with atherosclerosis and in the peripheral blood of patients with psoriasis (PS).
Section snippets
IL-18R and ST2L as selective markers for human Type 1 and 2 cells, respectively
To define human ST2L and human IL-18R as stable subset specific markers of Type 1 and 2 human lymphocytes, respectively, we generated mAb against human IL-18R and ST2L [4]. To test the specificity of these antibodies, we polarised allogenic Th, Tc and NK lines and stained them with antibodies for cell surface ST2L or IL-18R. The cells were also stained for intracellular IL-4, IL-5 (NK only) and IFN-γ ST2L was expressed on IL-4-producing CD3+CD4+ Th2 cells and not on the IFN-γ producing Th1
HIV patients have more lymphocytes that express ST2L than IL-18R
To assess whether these markers can be used to monitor lymphocyte subset distribution in human disease, PBMCs from 22 HIV-1-infected (12 haemophilic patients who are long term non-progressors infected in the early 1980s and the rest were a mixture of seroconvertors, progressors and asymptomatics) and 21 HIV-negative individuals were stained for cell surface ST2L or IL-18R together with CD3 and CD4, CD8 or CD56. PBMCs from HIV-negative individuals were obtained either from blood donation by
Distribution of ST2L* and IL-18R+ NKT in patients with PS
Psoriasis (PS) is a common, polygenic, inherited disease that affects 2–3% of the world-wide population [26]. It is characterized by scaly, red cutaneous plaques that contain keratinocyte hyperproliferation with hyper- and para-keratotic differentiation, epidermal influx of neutrophils with tissue inflammation in the stratum corneum, endothelial cell activation and the presence of an inflammatory mononuclear infiltrate in the papillary dermis and in the epidermis [27], [28], [29]. While
Type 1 and 2 cells in atherosclerosis
Atherosclerosis is an important chronic inflammatory disease of the vascular system. The lesions of atherosclerosis occur chiefly in large elastic and muscular arteries and can lead to ischemia of the heart, brain or extremities, resulting in infarction. There is compelling evidence that T lymphocytes are a fundamental component of the histopathology of early and late lesions of atherosclerosis and antibody responses to modified lipids in atheroma are characteristic of the disease. Both CD4+
Conclusion
In this article we summarise some of our recent data of the investigation on the presence and balance of NKT1 and NKT2 cells in infection and inflammation. There is a skewing towards NKT2 cells during HIV infection and in mild to moderate PS. In contrast, there is a distinct elevation of NKT1 over NKT2 cells in the artherosclerotic plaque in patients undergoing surgery for anuerysm. Since NKT cells are increasingly shown to play an influential role in innate immunity, these findings suggest
Acknowledgements
This work received financial support from The Medical Research Council, The Wellcome Trust, The British Heart Foundation and the Chief Scientist Office, Scotland.
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