T cell differentiation Flashcards
components of a TCR
- antigen specific TCR = alpha-beta heterodimer
- associated CD4 or CD8 co-receptor
- part of CD3 complex
what is the function of CD4 and CD8 co-receptors?
- required for TCR cell to recognize the peptide bound to MHC on an APC
- CD8 recognizes MHC I
- CD4 recognizes MHC II
MHC restriction
- T cells are selected in the thymus for their ability to weakly bind self-MHC molecules
- Key factor in self/non-self discrimination: T cells will only recognize peptide bound to self MHC and MHC are the major proteins recognized as foreign in transplant rejection
what are the stages of T cell maturation in the thymus and where do they occur?
- T cells begin as double negative
- In cortex: positive selection => double positive
- In medulla: negative selection => single positive
thymocyte
early T cell precursor (CD3-CD4-CD8-)
how is the double positive T cell generated?
in the cortex:
RAG1/RAG2 gene expression => VJ recombination on alpha chain and VDJ recombination on beta chain => T cell with unique TCR/CD3+/CD4+/CD8+
what is the next stage in maturation for a double positive thymocyte?
positive selection in the cortex:
- cortical epithelial cells express MHC class I and II
- if a TCR binds to a self MHC, it survives (if it binds MHC II -> becomes CD4+ and if it binds MHC I -> becomes CD8+)
what is the next stage in maturation for a single positive thymocyte?
negative selection in the medulla:
- cortical epithelial cells express MHC class I and II
- autoimmune regulator (AIRE) transcription factor induces medullary epithelial cells to synthesize self proteins to be expressed in the MHC molecules
- if a T cell binds self-antigen/MHC => death or Treg
- if a T cell doesn’t bind self-antigen/MHC => survival
how is T cell self-reactivity managed in the periphery (3)
- cells that react with antigen in the absence of co-stimulation (aka self antigen) become non-responsive
- clonal deletion when T cells repeatedly encounter high levels of self-antigen in periphery
- T regs suppress self-reactive T cells
CD4+ helper T cells
- recognize MHC class II (extracellular)
- secrete cytokines to support other cells
- differentiate into Th1, Th2, and Th17 subsets
CD8+ cytotoxic T cells
- recognize MHC class I (intracellular)
- directly kill other cells
Th1 CD4+ T cells
- secrete IFN-gamma which promotes and activates macrophages (intracellular pathogens)
- secretes IL-2 which promotes T cells
- differentiation driven by IL-12 and IFN-gamma
- involved in autoimmune and chronic inflammatory diseases
Th2 CD4+ T cells
- secrete IL-4, IL-5, and IL-13 which promote IgE, IgG, and IgA class-switching and differentiation in B cells (helminth defense)
- secrete anti-inflammatory IL-10
- differentiation driven by IL-2 and IL-4
- involved in allergies
Th17 CD4+ T cells
- produce IL-17 to promote neutrophils in response to extracellular pathogens/fungi
- enhance mucosal immunity
- differentiation driven by TGFB, IL-6, IL-1, IL-23
- involved in autoimmune and other chronic inflammatory diseases
Tregs
- inhibit CD4+ and CD8+ T cell functions
- CD4+CD25+
- express FoxP3 (decreased cytokine transcription) and CTLA-4 (inhibitor of T cell B7:CD28 co-stimulation)
- secrete anti-inflammatory IL-10 and TGFB
CD8+ T cells
direct cellular killing:
- release perforins which form membrane channels
- release granzymes which are cell membrane proteases
- activate caspases => apoptosis
- express FasL which binds to Fas on target cells => apoptosis
two signals in T cell activation (general)
- antigen recognition in the context of MHC by the TCR
- ITAM phosphorylation => recruitment and activation of ZAP70 tyrosine kinase => signaling cascade - binding of activating co-stimulatory molecules or cytokines to CD28 or cytokine receptors
two signals in CD4+ T cell activation
- TCR recognizes antigen on MHC II
2. APC B7 binds T cell CD28
two signals in CD8+ T cell activation
- TCR recognizes antigen on MHC I
2. cytokines (IL-2) from activated CD4+ T cell
T cell inhibitory molecules
CTLA-4: blocks binding of B7 to CD28 and inhibits IL-2 synthesis
PD1: expressed on T cells and interacts with PDL1 receptors on APC’s => inhibited immune response
T cell superantigens (examples and mechanism)
directly bind TCR and MHC class II without internal processing => activation of many T cells at once regardless of antigen specificity => uncontrolled cytokine release (IL-2, IL-1, TNF)
memory T cells
antigen specific T cells that have gone through a first primary response to antigen and on subsequent antigen recognition, activated with lower level of stimulation and a more rapid/robust response
