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Regulation of Newly Generated T Cells in the Setting of Lymphopenia by Btla and PD-1
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- Author / Creator
- Adegoke, Adeolu
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Recent thymic emigrants (RTE) are newly generated T cells that have just been exported to the periphery, where they continue their maturation to become mature T cells. RTE have only undergone central tolerance in the thymus but not yet undergone peripheral tolerance. As such, it is imperative that these T cell subsets are well regulated to prevent autoreactivity. Having previously shown by our group that coinhibitory T cell receptors such as PD-1 and Btla are required for establishing tolerance in newly generated T cells during lymphopenia, we investigated what stage during T cell development these coinhibitors are required to prevent autoimmunity. Deletion of the Btla gene in hematopoietic stem cells that otherwise had the potential to express this coinhibitor generated autoimmunity in lymphopenic recipient mice (p=0.02) once RTE began to seed the periphery. Likewise, deletion of PD-1 or Btla in the RTE that otherwise expressed these coinhibitors resulted in autoimmunity, p=0.02 and p = 0.0002, respectively, in lymphopenic recipients. Thus, our data showed that these coinhibitors are required to block autoimmunity at the RTE stage. Given the abundance of RTE in neonatal mice, we hypothesized that, unlike adult splenocytes that contain a fraction of RTE, neonatal splenocytes would induce autoimmunity during lymphopenia in the absence of PD-1 signaling. Supporting our hypothesis, our data showed that PD-1–/– neonatal splenocytes induced autoimmunity in adult lymphopenic mice. We further examined what T cell subsets are required for disease generation in the absence of Btla signaling and found the CD4 T cells and MHCII are required for disease generation.
Since Btla is constitutively expressed in T cells, we examined whether Btla signaling influences other coinhibitors in regulating T cell functions. In this study, we explored coinhibitory receptors that regulate T cell function. We found an inverse relationship between CD5, another coinhibitor that is constitutively expressed on T cells, and Btla in T cell ontogeny.
To model the disease relapse that occurs in some multiple sclerosis (MS) patients treated with lymphopenia-inducing antibody (anti-CD52) and given our data that PD-1 is required to prevent autoimmunity by RTE during lymphopenia, we asked if deficiency of PD-1 signaling prevented treatment of experimental autoimmune encephalomyelitis [(EAE), a mouse model of MS] by anti-CD52. Induction of EAE and subsequent treatment with anti-CD52 antibody once the mice became sick resulted in an increased proportion of newly generated T and B cells and double negative T cells. To our surprise, PD-1 signaling was dispensable for recovery from EAE following anti-CD52 antibody treatment. The rapid repopulation of RTE in the anti-CD52-treated mice prompted us to ask if the thymus played a role in the recovery. Interestingly, when the thymus was removed in the EAE-induced mice, two-thirds (p=0.001) of these mice had a relapse following anti-CD52 antibody treatment. We concluded that a functional thymus is required to prevent relapse in EAE-induced mice treated with anti-CD52. As such, continuous monitoring of thymic functions and lymphocyte counts in the clinic would benefit multiple sclerosis patients treated with anti-CD52.
Overall, this work showed the benefit of continuous thymic export of RTE and the important role Btla and PD-1 plays in blocking autoimmunity in these RTE under lymphopenic settings. -
- Graduation date
- Spring 2023
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.