Hu T cell Lectures

T cell maturation site

•Thymus is the major organ for T cell maturation

•Thymus provides the environment and stimulating signals for T cell proliferation and maturation

•The majority of thymocytes differentiate to alpha beta T cells; very few differentiate into gamma theta cells 

Double negative cells

no CD4 or CD8

Double positive cells

both  CD4 &CD8

T cell maturation Process

1)Progenitor T cells

→ Double negative

→Rearrangement of  TCRbeta chain

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2)Pre T-cells

→Double positive

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3)Immature T cells 

→Rearrangement of TCRalpha chain

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4)Mature T cells

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→Single positive 

TCR (T cell receptor) rearrangement

1) alpha chain: V,J

2) Beta chain: V,D,J

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VDJ= variability, diversity and joining 

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•Beta chain occurs first

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•alpha chain occurs second

Thymus selection

negative and positive selection

Positive selection

MHC restriction (CD4 or CD8)

MHCI: CD8+

MHC II: CD4+ 

Negative selection

when moderate degree of binding leads to positive selection, TCRs that bind **too strongly** are destined to cell death, thereby eradicating immature t cell that have high likelihood of attacking our own cells

Alpha beta T cell and Gamma Theta T cell

•TCR difference

•In vivo distribution, antigen recognition, CD4/8 expression diversity

•Alpha beta T cell for adaptive immune response 

• Gamma theta T cell for innate immune response

CD4+ T Cell & CD8 T cell

•mature alpha beta T cells only express CD4 or CD8

•Other cell phenotypes can also express CD4 or CD8

•CD4+ T cells will differentiate to T helper cells and T regulatory cells after antigen recognition

•CD8+ T cells will differentiate to cytotoxic T cells

Naive T cell

•G0 cycle, short life span

•No interaction with antigen

•Express CD45RA and high level L selectin, re circulate in the lymphatic systems

•Function: Recignize antigen

•After antigen presenting cells stimulation, it can differentiate to effector t cells and memory t cells 

Effector t cells

•G1 cycle, short life span

•Express high level IL2 receptors 

•Come from Naive t cell or t memory vells after antigen restimulation

•Differentiate to Th cells, Treg cells, or CTL (CD8+ T)

•Express integrin proteins and adhesion molecules to migrate to infection/inflammation site 

Memory t cells

•G0 cycle, extremely long life span of years

•Re stimulated by the same antigen

•Express high level IL2 receptors

**•Differentiation into effector t cells and memory t cells**

•Express integrin proteins and adhesion molecules to migrate to infection/inflammation site 

T helper cell

•Results from CD4+ cell differentiation 

•Th1, Th2, Th17

•Th1 for cell immunity, Th2 for humoral immunity 

•Th17: express IL17 for immune response 

T regulatory cells

•Highly express CD25 and Foxp3

•Negatively regulate immune activation for self tolerance

Cytotoxic T cells

•Resulted from CD8+ cell differentiation

•Th1, Th2, Th17 helper cells facilitate CTL’s proliferation and differentiation 

•Kill the infected cells or tumor cells through direct contact

•In very few cases, cytotoxic t cells could be CD4+ effector t cells 

Two signals requirement in T cell activation

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1. TCR-(Antigen-MHC complex)
2. Adhesion molecules→ enhanced adhesion, immunological synapses

CD8+ T cell: killing mechanism

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•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 cells; perforin, granzymes

→Exocytosis of granule contents

Perforin action: pore forming

Granzymes act as nucleases (apoptosis)

→Fas ligand to Fas triggers target cell death (mediated by caspase)

Dissociation

→Cytotoxic Cd8+ cells interact for about five minutes

→Dissociates and can conjugate with other target cells

TCR T Cells

•T cell receptor

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•Requires MHC matching

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•require 1 antigen on target

CAR T Cells

•Chimeric Antigen receptors

•Single fusion molecule with antigen specificity plus signaling domain

They are made by collecting T cells from the patient and re-engineering them in the laboratory to produce proteins on their surface called chimeric antigen receptors, or CARs. The CARs recognize and bind to specific proteins, or antigens, on the surface of cancer cel

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•MHC independent 

•Require 100 antigen on target

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Advantages:

•Live drug

•Tumor recognition independent of antigen presentation

•Multiple selection on antigen

•design flexibility 

 CD19/CD20 CAR-T cells for liquid cancer treatment

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CAR-T cells for liquid cancer side effects

•Cytokine release syndrome- Fever, myalgia, headache, anorexia, nausea, vomiting

•Graft- versus-host disease- Rash, diarrheam, hyperbilirubinemia

•Neurologic symptoms- confusion, Bcell aphasia, unresponsiveness, seizures

•Tumor lysis syndrome- hyperkalemia, hyperphosphatemia, hypocalcemia, hperuricemia

barriers for using CAR-T cells to treat solid tumors

•Immunosupressive pathways

•Physical barriers

•Metabolic restriction

•Immunosuppresive microenvironment 

Immunosuppressive cells

•Th17

•Treg

•TAM: tumor associated macrophage

•DCreg: regulatory dendritic cells

•TAN: Tumor associated neutrophil