The Hsieh laboratory is interested in understanding the mechanisms that lead to immune tolerance to both self-antigens involved in autoimmune disease, as well as non-self-antigens from antigens that come from the environment such as commensal bacteria or food. We utilize TCR repertoire analysis and germ-free mice to study T cell tolerance. A better understanding of how the immune system develops tolerance may be relevant for understanding autoimmune disease, food allergy, and inflammatory bowel disease.

We have two overarching interests:

  1. Understanding CD4 T cell responses to commensal bacteria, food, and self in the gut.  A recent example is from Dr. Russler-Germain’s discovery of a commensal Cryptosporidium1.
  2. Utilizing peptide-MHCII chimeric antigen receptors as a potential treatment for autoimmunity.  If successful, this would selectively eliminate the pathogenic T cells without resulting in immuno-suppression2.


  1.  Russler-Germain EV, Jung J, Miller AT, Young S, Yi J, Wehmeier A, et al. Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections. Immunity. 2021;54(11):2547-64 e7.
  2. Yi J*, Miller AT*, Archambault AS, Jones AJ, Bradstreet TR, Bandla S, et al. Antigen-specific depletion of CD4(+) T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity. Sci Immunol. 2022;7(76):eabo0777.

Cover submitted (unsuccessful) for paper on a “commensal” cryptosporidium (Immunity 2021). It is intended to represent that the major target of the immune system is due to cryptosporidium (purple ovals attached to ‘Immunity’ in this sea of food and bacteria in the small intestine. 

Cover submission (unsuccessful) for Science Immunology (2022). It is intended to show an anthropomorphized neuron with many antigens (different puzzle pieces) being attacked by CD4 T cells in red and protected by antigen-specific CAR T cells in blue. Puzzle pieces also allude to difficulty of knowing which self-antigens drive autoimmunity.

Mangled Myelin. This month’s cover depicts a normal myelin sheath wrapped around the axon of a neuron next to a damaged myelin sheath impairing nerve function. Autoreactive T cells specific for epitopes in myelin proteins trigger demyelination in human multiple sclerosis and mice with experimental autoimmune encephalomyelitis (EAE). Yi and Miller et al. report that chimeric antigen receptor (CAR) T cells displaying a complex of MHC class II and a peptide from myelin oligodendrocyte protein (MOG) selectively target pathogenic T cells for elimination in mouse EAE initiated by MOG immunization, thereby preventing and treating autoimmune symptoms. Using CAR T cells with different functional efficacy, the authors found that higher affinity autoreactive T cells are required for initiation of disease onset but lower affinity cells are sufficient to maintain ongoing disease.