summary for T-cells

Genetics & Immunology Exam III

what is the major organ for T cell maturation

thymus

what does the thymus provide during T cell maturation

environment that is stimulating signals for proliferation and maturation

true or false: majority of thymocytes differentiate to αβ T cell and very few differentiate to γδ T cells

true

what are the two types of cells that TCR α-chain cells can rearrange to 

CD4 SP (CD4+, CD8-, CD3hi) and CD8 SP (CD4-, CD8+, CD3hi, HSAlo)

progenitor T cells

rearrangement of TCRβ chain. CD3- TCR- CD4- CD8-

Pre-T cells

CD3+ TCRpTα:β- CD4+ CD8+

immature T cells

rearrangement of TCRα chain. CD3+ TCRαβ+ CD4+ CD8+

mature T cells

CD3+ TCRαβ+ CD4+

CD3+ TCR αβ+ CD8+

what are the two important events in T cell maturation in the thymus

TCR (T cell receptor) rearrangement and thymus selection: negative and positive selections

T cell maturation in the thymus steps

double negative→TCR rearrangement → double positive → thymus selection → single positive

VDJ

variability, diversity, joining

TCR rearrangement β chain 

D-J joining → VDJ (DNA) → VDJ-C (RNA) → VDJC (mRNA)

TCR rearrangement α chain

VJ (DNA) → VJ-C (RNA) → VJC (mRNA)

which chain goes under TCRm rearrangement first

Beta 

positive selection in the thymus

MHC(major histocompatibility complex) restriction (CD8 SP and CD4 SP).

negative selection in the thymus 

self-tolerance (cell death)

is this positive or negative selection in the thymus: fundamental step in the generation of a responding T cell repertoire: only those T cells survive that recognize human peptides (MHC) presented on the surface or cortical thymic epithelial cells (cTEC) with a moderate affinity. T cells who cannot recognize MHC will undergo apoptosis (95%).

positive selection 

is this positive or negative selection in the thymus: important to prevent T cells attacking our own cells. TCRs that bind too strongly to MHC complexes in thymus, the intracellular singing is so strong that it leads to cell death, thereby eradicating immature T cell that have a high likelihood of being self-reactive and attacking our own cells 

negative selection

steps of MHC recognition (positive selection)

DP cells TCR recognize and bind to MHC I → CD4 expression will be shut down → CD4-CD8+ T cells OR  DP cells TCR recognize and bind to MHC II → CD8 expression will be shut down → CD4+CD8- T cells 

CD8 T cell features

MHC I binding, cytotoxic effector cells

CD4 Th1 cells

MHC II binding, effectors activate macrophage, CTLs, and induce B cells to produce opsonins (proteins that tag foreign particles, such as bacteria, and dead or dying cells, marking them for destruction by immune cells like phagocytes)

CD4 Th2 cells

MHC II binding, activate B cells to produce multiple antibody classes

how do T cells recognize the antigen peptide-MHC complex

double recognition: T cells have dual specificity so they recognize both self-major histocompatibility complex moles (MHC I or II) and peptide antigens displayed by those MHC molecules. Additionally, MHC restriction

how do T cells know when to activate, proliferate, and differentiate

two signals: complete activation requires two signals. 1) delivered through antigen-specific T cell receptor (TCR) 2) generated by cognate interactions through adhesion molecules of T cells and antigen-presenting cells and/or by cytokines produced by antigen-presenting cells

what happens if a peptide binds to another MHC molecule that is not compatible

no T-cell recognition occurs.

what restricts the recognition between T cells and APCs

MHC types

which MHC restricts the recognition between CD4+ T cells TCR & antigen peptide

MHC II

which MHC restricts the recognition between CD8+ T cells TCR & antigen peptide

MHC I

adhesion molecules

enhance adhesion due to immunological synapses

what is the killing mechanism of cytotoxic CD8+ cells

conjugate formation, membrane attack, dissociation, target cell death

conjugate formation

cell adhesion, recognition of MHC I-antigen peptide on target cells

membrane attack

granules in cytotoxic CD8+ T cell: Perforin, Granzymes), exocytosis of granule contents (perforin: pore forming, granzymes act as nucleases), Fas ligand to Fas triggers target cell death

dissociation 

cytotoxic CD8+ cells interact for about five minutes, dissociates and can conjugate with other target cells 

target cell

target cell dies after several hours

perforin

pore formation on the cell membrane to induce cell lysis

granzyme

enters target cell and induced cell apoptosis

Fas-FasL pathway

Fas and FasL are induced upon T cell activation and mediated by Caspase

how do CD19/CD20 CAR-T cells differentiate between TCR T cells

CAR T cells have been genetically engineered to target surface antigens like CD19 and CD20 directly, by passing the normal T-cell receptor (TCR) system that requires the antigen to be presented by a MHC molecule

CD19

cell surface protein whose expression is restricted to B cells and B cell precursors, not expressed on HSC, and is expressed by most B-cell malignancies

common side effects of CAR-T cell therapy 

cytokine release syndrome, graft-versus-host disease, neurologic symptoms, tumor lysis syndrome 

barriers for CAR-T cells in solid tumor treatment

barriers against immunotherapy: immunosuppressive pathways, physical barriers, metabolic restriction, immunosuppressive microenvironment

immunosuppressive cells in solid tumor

MDSC(myeloid-derived suppressor cell), Th17 (T helper 17 cells), Treg (T regulatory cells), phenotypic and functional switch of immune cells: TAM (Tumor-associated macrophage), DCreg (regulatory dendritic cells), TAN (tumor-associated neutrophil)

M2 macrophage

immunosuppressive, pro-tumorigenic, anti-inflammatory 

M1 macrophage

pro-inflammatory, cytotoxic, anti-tumorigenic 

M3 macrophage

immunosuppressive, pro-tumorigenic