T cell activation

Question 1

T cell activation facts

Answer 1

• APCs are required
  
  • Signal 1 = MHC/peptide interaction w/ TCR
  • Signal 2 = CD80/86 (aka B7 - on APC) interaction w/ CD28 (on T cell)
  • Signal 3 = cytokines!
• This all leads to T cell proliferation, differentiation, and survival

Question 2

T cell inhibition w/ CTLA4

Answer 2

• Relies on CTLA4 inhibitory receptor, which is a homolog of CD28
  
  • Has a higher affinity for CD80/86/B7 than CD28
  • When it binds CD80/86/B7 → inhibition T cell proliferation, cell cycle progression, and IL-2 synthesis
• CTLA4 is expressed on CD4+ and CD8+ T cells after activation (difference from CD28, which is constitutively expressed on all T cell subsets regardless of activation)
  
  • Exception: CTLA4 is constitutively upregulated in Tregs, but the exact mechanism is being worked out
  • Probably serves as an internal checkpoint to regulate and attenuate immune responses (via CD28) if need be

Question 3

T cell inhibition w/ PD-1

Answer 3

• PD-1 is more widely expressed than CTLA4 (found on monocytes, B, T, and NK cells)
• It’s major fxn is limiting autoimmunity and T cell activity in peripheral tissue in response to infection
  
  • PD-L1 (on “APCs”) binds PD-1 → T cell inactivation, tolerance, and/or anergy
• Tumor cells exploit this fxn byexpressing PD-L1 and by inducing PD-1 expression on tumor-specific T cells → inhibition of tumor-specific T cells → immune resistance by tumor microenvironment