T Cells Flashcards
What are T cells and what is their role?
Lymphocytes generated in the thymus
Recognise antigen that is degraded as peptide fragments and presented on MHC (via TCR)
2 types
- cytotoxic T cells (CD8) kill virally infected somatic cells and tumour cells
- Helper T cells (via cytokines and cell contact signals, CD4)
Also play a role in allograft rejection
Describe the T cell receptor
Has two chains (alpha and beta)
Always membrane bound (not secreted like Ig)
Also has variable and constant region
Associated with CD3 signalling chains on the T cell
Recognise peptide presented on MHC
What is the role of CD4/CD8 on the T cell
Determines the function CD4 can recognise MHC class II on APCs CD8 can recognise MHC class I on all somatic cells (excepts RBCs)
Describe the 3 stages of T cell maturation in the thymus
1) migration to the thymus (from thebone marrow, or FOETAL LIVER)
2) Differentiation via TCR gene rearrangement, expression of both TCR (VDJC genes, on chromosome 7 and 14), CD4 and CD8
3) selection –> learn to respond to MHC (approx 95% die)
- strong binding–>deletion (autoimmunity)
- not binding MHC–> deletion (useless T cells)
- weakly bind MHC I selected as CD8, weakly binding MHC II selected as CD4
T cells migrate through thymus cortex–>medulla–>periphery
Thymic output greatest before puberty (then decreases with age)
Which cells in the thymus are responsible for positive and negative selection of the T cells
Positive selection occurs on the thymic epithelial cells in the cortex
Negative selection occurs in both the cortex and medulla by BM derived DCs and macrophages (also some medullary epithelial cells)
Describe the role of AIRE
Autoimmune regulatory genes
Expression of tissue specific antigen occurs at low levels in the thymus (medullary epithelial cells) to induce deletion of high affinity T cells and promote Treg cells
What are the cause and features of Autoimmune Polyendocrine Syndrome Type I?
previously called APECED= autoimmmune polyendocrinopathy with candidiasis and ectodermal dystrophy
- AR disorder with mutation in AIRE gene –> failure to express tissue specific antigen–>failure to delete T cells specific for multiple tissue antigens–>autoimmunity–>lymphocytic infiltration of multiple tissues with multiple autoantibodies
Three cardinal manifestations 1) chronic mucocutaneous candidiasis, candida is controlled by Th17 cells which secrete IL-17 and IL-22 (autoimmunity to these in APS Type I) 2) autoimmune hypoparathyroidism 3) autoimmune addison's disease \+can be other autoimmune manifestations
What is the necessity of peripheral tolerance, and which cells are responsible for promoting it?
Alternative means for maintaining tolerance outside the thymus to deal with T cells that escape the process, self antigen not expressed in the thymus and food antigen/commensal organisms and environmental antigens
Suppression by Treg cells
What are the features of a Treg cell and what is the role of Foxp3?
CD4pos cells (also CD25+) 10-15% of peripheral CD4 cells express transcription factor Foxp3 (influences genes, reinforces regulatory phenotype (CTLA4, IL-10), blocks transcription of IL-2, responsible for development and function of Treg cells Lack of Foxp3--> autoimmunity, allergy and lymphoproliferation
What are the cause and features of IPEX?
IPEX= immune dysfunction, polyendocrinopathy, enteropathy, X-linked
Defect in Foxp3 (no regulation by Treg cells–>autoimmunity and allergy)
- frequently fatal, presents forst few months of life
- endocrinopathy: diabetes, thyroiditis
- enteropathy–>FTT–>diarrhoea
- haemolytic anaemia
- ITP
- autoimmune neutropenia
- atopic features: eczema, food allergy, eosinophilia
- lymphadenopathy, splenomegaly
What are the mecahnisms of suppression of the Treg cell?
- CD25 mops up IL-2 and restricts access by conventional T cells
- CTLA4, inhibitory signalling molecule expressed late on activated T cells to limit their expansion (down regulates CD80/CD86 (B7) on APC)
- induction of inhibitory cytokines by DCs (IL-10 and TGFbeta)
- secrete inhibitory cytokines IL-10, TGFbeta, IL-35, IL-9
- cytolysis of other cells (Macrophages, T cells) via granzyme B, perforin
Preferred locations of naive, mature and memory T cells?
Naive T cells preferentially circulate through the LNs where they can encounter activating signals
Mature T cells leave the thymus and circulate through the LNs looking for MHC+foreign peptide on APCs
Memory T cells preferentially circulate through the tissues where they can be activated and more easily engage effector function
Which cytokine results in T cell clonal expansion (autocrine pathway)
IL-2
What is required for T cell activation?
presentation of peptide in MHC
AND
co-stimulation, mediated by B7.1 and B7.2 interacting with CD28 amd CTLA-4
–> foreign
absence of costimulation–> tolerance
What are the essential co-stimulatory molecules on APCs that interact with T cells, and what do they interact with on the T cell?
CD80 (B7-1) and CD 86 (B7-2)
Bind and stimulate CD28–>activation of the T cell
OR
CTLA-4 on the T cell–> generates a negative signal, delayed deactivation of the activated T cell, regulatory T cells to suppress
CTLA4 Ig used to block T cell activation in RA
Anti CTLA trialled in cancer Rx (SE autoimmunity)
OR
CD40ligand on T cell interacts with CD40 to activate the APC, express more B7 to activate other T cells
