CD1 molecules represent a class of antigen presenting molecules that present lipid antigens to cognate T cells. These molecules have been identified in all mammals examined so far. Unlike MHC molecules, which are highly polymorphic, CD1 molecules exhibit limited polymorphism and are divided in to two groups – 1 and 2. Group 1 CD1 comprises of CD1a, CD1b and CD1c while group 2 CD1 contains CD1d. Mice, the most commonly used animal model for immunological studies, only express CD1d while humans express all CD1 isoforms. Group 1 CD1 molecules are known to present both self and foreign lipid antigens to T cells, suggesting that group 1 CD1-restricted T cells have the potential to play an important role in infectious and autoimmune diseases as well as tumor immunity. However, due to the lack of group 1 CD1 expression in mice, the study of these T cells has lagged behind compared to the study of CD1d-restricted T cells. In order to overcome this challenge, our lab developed a transgenic mouse model harboring human CD1b and CD1c (hCD1Tg) molecules. Interestingly, a majority of group 1 CD1-restricted T cells isolated from this mouse were autoreactive, a finding similar to that of humans. In fact, about 1/10- 1/300 of all T cells in the PBMC of humans are group 1 CD1-restricted autoreactive T cells. Since in vivo tracking of group 1 CD1-autoreactive T cells was not feasible in hCD1Tg mice (in lieu of lack of tetramers available to identify these T cells), our lab generated a second transgenic mouse model expressing a CD1b-autoreactive TCR (HJ1Tg). This mouse was crossed to the hCD1Tg background to generate hCD1Tg/HJ1Tg mice. Using this mouse model, it was demonstrated that HJ1 T cells were capable of protecting against Listeria monocytogenes infection. However, the lipid antigens recognized by these T cells remained unclear. It was also surprising that in spite of harboring autoreactive T cells at a high frequency, the mice did not develop any overt autoimmune conditions. Given that hCD1Tg/HJ1Tg mice did not develop autoimmune diseases, we hypothesized that these T cells might be activated under conditions of hyperlipidemia, and thus contribute to downstream inflammatory process. To test this hypothesis, hCD1Tg/HJ1Tg mice were crossed onto the ApoE-/- background (hCD1Tg/HJ1Tg/ApoE-/-). This unique model not only allowed us to examine the role of CD1b-autoreactive T cells under conditions of hyperlipidemia but also examine their role in atherosclerosis, fatty deposition alongin arterial walls that developsfound in ApoE-/- mice. Interestingly, hCD1Tg/HJ1Tg/ApoE-/- mice, spontaneously developed severe psoriasis-like skin inflammation starting at about 20-25 weeks of age. Skin inflammation was characterized by T cell and neutrophil infiltration as well as a Th17 biased cytokine milieu. Consequently, anti-IL-17A administration ameliorated disease. In spite of the drastic skin phenotype, there was no difference in atherosclerotic plaque area in the absence or presence (ApoE-/- vs. hCD1Tg/HJ1Tg/ApoE-/- mice) of HJ1 T cells. Additionally, we also found that phospholipid and cholesterol species accumulated in diseased skin and that these lipids could be presented by CD1b to activate HJ1 T cells. Furthermore, hyperlipidemic serum caused increased IL-6 secretion by CD1b+ dendritic cells compared to normo-lipidemic serum. This heightened production of IL-6 skewed the HJ1 T cells to produce more IL-17A. Lastly, we demonstrated that CD1b expression was increased in psoriatic skin compared to normal skin of humans. Also, CD1a and CD1b-autoreactive T cells were detected at a higher frequency in psoriasis individuals compared to normal controls. These data indicated that CD1b-atuoreactive T cells contribute to a hyperlipidemia-induced psoriasis-like skin inflammation. Furthermore, our findings suggested that group 1 CD1-restricted autoreactive T cells could serve as a bridge linking hyperlipidemia, inflammation and subsequent downstream autoimmune pathologies. In an attempt to identify lipid antigens recognized by HJ1 T cells, we found that tumor-derived lipids from human and murine T cell lymphoma cells activated HJ1 T cells to a greater extent than equivalent amounts of lipids isolated from normal human and murine T cells. Therefore, we explored the role of CD1b-autoreactive T cells in the context of tumor immunity. It is known that tumors harbor neo-lipid species. Therefore, group 1 CD1-restricted T cells could respond to these lipids when presented by group 1 CD1 molecules. Their activation could have potential anti-tumor effects, because group 1 CD1-restricted T cells can produce Th1 related cytokines important in anti-tumor immunity. Interestingly, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), a potent anti-tumor agent. Lastly, we demonstrated that the adoptive transfer of HJ1 T cells conferred protection against a CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the anti-tumor effect. Thus, this study, for the first time, demonstrated the anti-tumor potential of CD1b-autoreactive T cells and their possible potential use in adoptive immunotherapy

Last modified

• 02/20/2018

Creator

• Sreya Bagchi

DOI

• https://doi.org/10.21985/N2SH5Q

Subject

• Driskill Graduate Training Program in Life Sciences

Keyword

• Immunology

Date created

• 2016-01-01

Resource type

• Dissertation

Rights statement

• In Copyright