The effect of CLTA-4 on effector to memory differentiation of CD8 T cells
Open Access
- Author:
- Mullikin, Kiki Lorraine
- Area of Honors:
- Veterinary and Biomedical Sciences
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Dr. Vandana Kalia, Thesis Supervisor
Robert John Vansaun, Thesis Honors Advisor - Keywords:
- CTLA-4
CD8 T cell memory
LCMV
Tregs
effector - Abstract:
- Acute viral infection leads to the formation of long lasting memory cells whose numbers and functionality are products of signals received throughout infection. Regulatory T cells (Tregs) modulate the extent of effector CD8 T cell proliferation and differentiation to prevent autoimmunity and overly exuberant immune responses that result in excessive tissue damage. Tregs express CTLA-4 as one mechanism to modulate the immune response; CTLA-4 binds to B7 molecules and decreases the sensitivity of effector cells to antigen. We hypothesized that administration of CTLA-4 in vivo during development of the effector response would mimic the effect of Tregs, limit proliferation of CD8 T cells, and improve memory quality by increasing the number of surviving memory precursors. Treatment with CTLA-4 during priming produced a defect in overall expansion. The number of memory precursors decreased, as did polyfunctionality and expression of Bcl-2. Treatment during pathogen clearance and peak expansion caused neither functional nor phenotypic differences. Treatment during contraction and early memory formation caused lower expression of GzmB and higher expression of Bcl-2 at day 15 and day 21 post infection, but these differences began to normalize by day 40 post infection. A peptide stimulation and recall demonstrated no functional differences in the memory CD8 T cells. Transfer of stimulated Tregs during contraction and early memory formation increased the survival of antigen specific CD8 T cells in vivo. Phenotypic and functional changes observed following various treatments during infection show that CTLA-4 modulation has important implications for the development of memory CD8 T cells. While treatment during effector contraction appeared to help memory formation, more work remains to learn to better exploit these differences. Optimized doses of CTLA-4, or similar agonists, could be co-administered with a vaccine regimen to increase memory cell production.