The CD1c lipid-presenting molecule is implicated in T cell immunity, but its absence in mice has limited in vivo investigations. To overcome this, we generated immunocompetent transgenic (Tg) mice expressing human CD1c (CD1c Tg). CD1c expression in these mice mirrored human distribution, defining conventional dendritic cell 2 (cDC2), monocyte-derived dendritic cells (moDCs) and B cell subsets, and functionally supporting lipid antigen presentation.
In vitro bone marrow derived CD1c Tg DCs directly stimulated CD1c-restricted T cells specific for the self-lipid antigen methyl lysophosphatidic acid (mLPA), whereas B cells did not unless preloaded with mLPA, recapitulating the antigen-presenting cell (APC) behaviour observed in humans.
We further show that CD1c Tg mice developed peripheral CD1c self-reactive T cells at a detectable frequency of approximately 1 in 100,000 T cells. Stimulation of CD1c Tg splenocytes with autologous CD1c+ DCs enhanced the detection of these T cells, suggesting a role for peripheral activation and expansion.
Retrogenic mice expressing a CD1c-restricted, mLPA-specific TCR (DN4.99) confirmed that CD1c expression on thymocytes is necessary and sufficient for the selection and development of CD1c-restricted T cells. Phenotypic analysis of the retrogenic TCR T cell repertoire revealed a dominant central memory phenotype, while a minor subset retained a naïve-like profile.
Finally, CD1c expression on APCs and the presence of CD1c self-reactive T cells did not affect the onset, penetrance, or severity of experimental autoimmune encephalomyelitis (EAE), a model of autoimmune inflammatory disease in which self-lipid-specific T cells have been implicated. Furthermore, DN4.99 TCR T cell transfer into sublethally irradiated CD1c Tg mice did not reveal major systemic toxicity and only transient mild perturbation of CD1c+ B cell and DC repopulation. Collectively, these results show that CD1c Tg mice are a valuable model to characterize CD1c-restricted T cell response, and support the safety of CD1c-redirected adoptive cell therapy, warranting further investigation for clinical translation.