CD4 T Cells

T cell activation needs 3 signals:

1. Signal 1 = MHC/Peptide + TCR

2. Signal 2 = Co-stimulation (B7) on DC engages CD28 on T cell

3. Signal 3 = Cytokine secretion by APC

The 3 signal are delivered from __________ to __________

T cell to APC

Based on _________, T cells can differentiate to different effector T cells

Signal 3

Different effector cells:

T_H1, T_H2, T_H17, T_FH, and T_reg

T_reg cells signal 3 cytokine

TGF-β

T_FH cells signal 3 cytokine

IL-6

T_H17 cells signal 3 cytokine

TGF-β and IL-6

T_H1 cells signal 3 cytokine

IL-12 and IFN-γ

T_H2 cells signal 3 cytokine

IL-4

T_reg transcription factor

FoxP3

T_FH transcription factor

Bcl6

T_H17 transcription factor

RORγT

T_H1 transcription factor

T-bet

T_H2 transcription factor

GATA3

T_reg secreted cytokine

TGF-β and IL-10

T_FH secreted cytokine

IL-21 and ICOS

T_H17 secreted cytokine

IL-6 and IL-17

T_H1 secreted cytokine

IL-2 and IFN-γ

T_H2 secreted cytokine

IL-4 and IL-5

CD8 function

Kill virus infected cells

CD4 T_H1 function

Activates macrophages and provide help to B cells for AB production

CD4 T_H2 function

Provide help to B cells for AB production, especially switching to IgE

CD4 T_H17 function

Enhance neutrophils response and promote barrier integrity (skin/intestine)

CD4 TF_H function

B cell help, iso-type switching, and AB production

CD4 T_reg function

Suppresses T cell responses

CD8 targeted pathogen

Viruses and some intracellular bacteria

CD4 T_H1 targeted pathogen

Microbes that persists in macrophages vesicles 

CD4 T_H2 targeted pathogen

Helminth and parasites

CD4 T_H17 targeted pathogen

Fungi

CD4 T_FH targeted pathogen

All types

T_H1 cells

Activate macrophages which increase CD40 and TNF receptor expression, IFNg (from T cells) along TNFa promote anti-microbial activity from the macrophages

Granuloma

The initiated inflammatory response if pathogen persists in macrophages. Walls off and contains the infected cells

Pro-inflammatory

T_H1 with cytokines IFNγ and TNF-α

Anti-inflammatory

T_H2 with cytokines IL-4 and IL-5

What can different subsets of effector T cells do?

Modulate the effector functions of others

Can Treg CD4 T cells be grown in vitro for clinical use?

Yes, they can be used for in vitro for clinical use

T_reg CD4 T cells

Used to be called suppressor cells and can act through secretion of suppressive cytokines. They are needed to control autoimmunity and scavenge IL-2 for activation induced cell death (AICD) of activated T cells.

Suppressive cytokines

IL-10, TGF-β, OR killing effector T cells OR targeting DC OR IL-2 scavenging

FoxP3

Key transcription factor, knocks-out develop autoimmunity, CTLA4 knockouts have similar phenotype

2 ways for development of T_reg cells

Thymic T_reg and induced T_reg (periphery)

T_reg development

Occurs during thymic development OR after activation in secondary lymphoid organs (SLO)

Self reactive T cells

Most deleted in thymus (AIRE-dependent presentation of self specific proteins), only a small percent will become T_reg in thymus

What hapens once in thye are in the SLO?

Peripheral tolerance, the induction of non-responsiveness in T cells that see self-AG (Anergy and active process —> T cell mediated (T_reg)

T regulatory (T_reg) cell development

Develop in thymus and the TCR has intermediate affinity for self antigen. Also up regulates FoxP3

FoxP3+ T_reg 

Prevent autoimmunity

Molecular mechanisms for T cell suppression

Inhibitory cytokines, cytolysis, metabolic disruption, and targeting dendritic cells

T_reg _________ and _________graft

Suppress and decrease

CD8 cytotoxic T cells

Inflammatory, secretes cytotoxins (perforin, granzymes, and granulysin) and cytokines (IFN-γ and TNFa)

CD8 T cells responses

Activation and proliferation (Signal 1,2, and 3), become killers (CTL), have lyticgranules (perforin, granzymes, and granulysin) and fas ligands. Secrete pro-inflammatory cytokines (IFN-γ and TNFa)

APCs deliver three kinds of signals to naive T cells

1. Activation

2. Survival

3. Differentiation

Pro-inflammatory cytokines

Interferon gamma (IFN-γ) and TNFα

Interferon gamma (IFN-γ)

Inhibits viral replication, increases MHC l and peptide processing, and activates macrophages and NK cells

TNFα

Fever, acute phase response, and contributes to macrophage activation

Lytic granules

Perforin, granzymes, and granulysins

Perforin

Aids in delivering contents of granules into the cytoplasm of target cell

Granzymes

Serine proteases, which activates apoptosis once in the cytoplasm of the target cell

Granulysins

Has antimicrobial actions and can induce apoptosis

Mice do not have

Granulysins

Killing is ______________ and ________________

Contact dependent and quick

Recently activated effectors are____________

Distributed throughout body

FAS: FAS ligand (FasL) mediated killing

FasL is up-regulated on activated CD8 T cells and binds FAS on a target cell. They kill via apoptosis and takes longer than perforin/granzymes pathway

CD8+ cytotoxic T lymphocytes (CTL)

Kill target cells while sparring uninfected neighboring cells

Longevity of T cell memory

Smallpox exposure/vaccination induces memory CD4 and Cd8 T cells that can last more than 60 YEARS

Memory T cells

There are different kinds of memory T cells: Central memory (Tcm), effector memory (Tem) and resident memory (Trm)

Central memory (Tcm)

Recirculate through SLO, have high expression of molecules associated with entry LN (CCR7 and CD62L)

Effector memory (Tem)

Found in non-lymphoid tissue, consistently express effector molecules

Resident memory (Trm)

Go to tissue and stay there, does not leave organ