Pivotal role of co-inhibitory molecules in immune tolerance

• Author / Creator

  Thangavelu, Govindarajan

• The main function of co-inhibitory molecules is to regulate T cell immune responses by providing negative signals to those cells. Homeostatic activation of T cells occurs in both natural and artificially induced states of lymphopenia. Although lymphopenia leads to homeostatic proliferation of T cells, it does not always lead to autoimmunity, suggesting that control mechanisms may exist. Controlling these mechanisms may be particularly important during the period when the first T cells are exported from the thymus, as many recent thymic emigrants (RTE) have not yet had the opportunity to undergo peripheral tolerance. In chapters 2 and 3, I tested whether the major function of the co-inhibitory receptors such as programmed death-1 (PD-1) and B and T cell attenuator (BTLA) is to control autoimmunity induced by homeostatic activation, and also to assess their importance in RTE vs. established peripheral T cells. Interestingly, I found that their function is more critical only in newly generated T cells but not in mature T cells as PD-1-/- or BTLA -/- RTE induced a lethal multi-organ inflammatory disease in lymphopenic recipients. The disease induced by lymphopenia induced proliferation (LIP) was inhibited by reducing lymphoid space and also by providing polyclonal T cells as competitors for the pathogenic T cells. In chapter 4, I examined whether co-inhibitory molecules play a critical role in the "spontaneous" allograft tolerance of male islets. Among those tested, only PD-1 has a role in spontaneous acceptance of male islet allografts. While T cells have been observed to induce bystander killing of uninfected cells at the vicinity of the infected cells during viral infections in vitro, very little is known about the existence of bystander killing in vivo and also the mechanisms that limit this type of killing. In chapter 5, I investigated the capacity for bystander killing of islet cells in vivo and observed that PD-1, but not BTLA, can limit bystander killing. Overall, my studies have divulged the critical roles of co-inhibitory molecules in the maintenance of self-tolerance and these research findings will provide critical insights in the development of novel therapies to combat autoimmunity and rejection of transplants.

• Subjects / Keywords

  • Tolerance
  • Autoimmunity
  • Programmed Death-1

• Graduation date

  Fall 2011

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3K920

• 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.