Early quantitative and functional deficiency of NK1⁺‐like thymocytes in the NOD mouse

Abstract

An immunoregulatory role has recently been attributed to the discrete subset of major histocompatibility complex class I-restricted NK1+ mature heat-stable antigen- (HSA-) thymocytes expressing an unusual Vbeta8-biased T cell receptor repertoire. NK1+ T cells are the main interleukin (IL)-4 producers upon priming. We have studied the size and the function of this subset in the nonobese diabetic (NOD) mouse, a model of spontaneous T cell-mediated autoimmune insulin-dependent diabetes. This study was complicated by the absence in this strain of the NK1.1 allele, the only one for which an antibody is available. To circumvent this difficulty, the cells, hereafter designated the NK1+-like T subset, were characterized by the use of monoclonal antibodies which showed the Vbeta8 bias in the CD44+ Ly-49+ MEL-14- 3G11- thymocyte subset of non-autoimmune strains and of its absence in class I-deficient (beta2-microglobulin-/-) mice. A clear deficit in the number of NK1+-like cells was evidenced at 3 weeks of age in NOD mice. It was still present at 8 weeks of age in the double-negative CD4-CD8- population. The functional anomaly was even more striking: NOD mouse NK1+-like thymocytes virtually lacked the ability to produce IL-4 at 3 weeks and still showed a very reduced capacity at 8 weeks. NK1+ T cell deficiency was also suggested in the periphery by the reduction of Ly-49A+ cells in the spleen of 3- and 8-week-old NOD mice and the absence of short-term production of IL-4 in vitro by NOD mouse spleen cells 90 min after the administration of anti-CD3 antibody, a response attributed to NK1+ T cells. Taken together, these data demonstrate a very early defect in NK1+-like T cells which could be involved in the genesis of autoimmunity in NOD mice through a deficiency in Th2 cell function.

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

“…iNKT cells are reduced in number in diabetes-prone NOD mice [4,5], and increasing the number of iNKT cells by adoptive transfer [6,7] or via the introduction of a Va14-Ja18 transgene, reduces significantly the progression of the disease [6]. A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11].…”

Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers

“…CD1d-dependent NK T lymphocytes are a distinct T cell subset that may be important for the regulation of the immune response 3 4 5 7 9 42. Reliable cell surface markers that define this population have been lacking, however, and therefore it has been difficult to precisely enumerate these lymphocytes in ontogeny or during immune responses.…”

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

“…Autoimmunity in NOD mice is T cell-dependent [1,2], and a role for the thymus has been evoked. Specific deficiency in thymic NKT cells is relevant to the immunopathology seen in this mouse [6,7]; NOD thymocytes produce low amounts of IL-4 [8], respond poorly to cytokines [9] and are relatively insensitive to apoptotic signals [10,11]. Experiments with F1 chimeras showed that the hemopoietic-derived thymic microenvironment is essential for development of diabetes [12,13] and intrathymic injection of Langerhans' islets abrogates autoimmunity [14].…”