IMM: T Cell Activation

FoxP3

*#1*: A master transcription factor that is expressed by Treg. Without it, we don't have Treg cells and can't control CD4 Tcell activation.

TGFβ (Transforming growth factor beta)

*#2*: Secreted by activated Treg to suppress the CD4 T cell.

Treg

*Cell on left side*: Generated in the thymus (natural form) but also in the peripheral immune system (induced form) It is CD4+ CD25+ and expresses the transcription factor FoxP3 Recognize peptide-MHC class II on APC and *suppress the activation of standard CD4+ T cells*.

LFA-1 (Lymphocyte function associated antigen 1)

*Purple receptor*: This is an integrin. A T cell surface molecule that interacts with ICAM molecules to mediate T cell adhesion.

ZAP-70

*Yellow floating receptor*: A tyrosine kinase involved in TCR signal transduction. It is activated via phosphorylation by LCK. It has SH2 domains that bind to the phosphorylated ITAMs. This triggers three different signal transduction pathways in T cells that culminate in the activation of transcription factors which turn on the expression of new genes involved in T cell activation: 1) NFAT, 2) NFκB, 3) AP1 Patients can lack this molecule resulting in T cell immunodeficiency.

ICAM-1 (Intercellular adhesion molecule 1)

*brown rod receptor*: This is a cell surface molecule that interacts with LFA-1 to mediate T cell adhesion. Expressed on the surface of the endothelial cell. It helps mediate T cell entry to lymph nodes.

LCK

*darker green*: A tyrosine kinase involved in TCR signal transduction. It associates with the cytoplasmic tails of the CD4 and CD8 and phosphorylates the ITAMs of CD3 and ζTCR to start the signal transduction pathways.

CCL18, 19, 21

*green*: Chemokines that mediate attraction of T cells to lymph nodes. They are bound to the endothelial cell surface interact with chemokine receptors (CCR7) on the T cell surface resulting in an increase the avidity of an integrin (LFA-1) for ICAM-1 - *tighter binding*. Diapedesis and attraction toward APC in lymph nodes. It moves the T cell against the S1P gradient.

Fyn

*light green*: A tyrosine kinase involved in TCR signal transduction. It phsophorylates ITAMs in the CD3γ, d and e chains and in the TCRζ chain

L-Selectin

*orange circles*: Another class of T cell surface adhesion molecule that binds to this carbohydrate group on vascular addressins (CD34 and GLYCAM-1).

Addressins

*yellow circles*: Carbohydrate-bearing adhesion molecules, such as CD34 and GLYCAM-1. They are expressed on HEV endothelial cells, allows "rolling" of the T cell on the vessel wall. It helps mediate T cell entry to lymph nodes.

Integrins

Cell surface molecules such as LFA-1 that mediate T cell adhesion with other cells through interaction with immunoglobulin superfamily molecules such as ICAM-1

B7

In addition to a TCR signal, T cells must also receive a costimulatory signal on CD28 in order to become activated. This is the CD28 ligand, *expressed only on professional APC*, which thus acts as a costimulatory molecule. Toll-like receptors in innate immunity can upregulate this costimulatory signal (innate/adaptive connection).

T cell areas of secondary lymphoid organs

Once in blood, T cells pass from the blood circulation into these areas, which include paracortex of lymph nodes, central periarteriolar lymphatic sheath (PALS) of spleen, T-dependent areas of GALT. This is where T cells first encounter foreign antigen, which is presented by professional APCs like dendritic cells.

Src-family tyrosine kinases

Protein tyrosine kinases such as LCK and FYN.

Syk-family tyrosine kinases

Protein tyrosine kinases such as ZAP-70 that show structural homology to the prototypic family member, Syk

Anergy

Recognition of MHC /peptide in the absence of costimulation drives T cells into this state of prolonged hypo-responsiveness. After which, these T cells fail to become activated by MHC/peptide even when costimulatory signals are provided. This is an safe-guard adaptation that provides a mechanism to ensure tolerance to self antigens that are not presented to developing T cells in the thymus since these antigens will be presented by *nonprofessional APCs that cannot express costimulatory molecules*. Note: T cells need both TCR and CD28 stimulation for activation.

S1P1

SIP receptor

CD2 (LFA-2)

T-Cell surface immunoglobulin superfamily molecules that participate in T cell adhesion through mutual interaction. It interacts with other adhesion molecules, such as lymphocyte function-associated antigen-3 (LFA-3/CD58) in humans, or CD48 in rodents, which are expressed on the surfaces of other cells. In addition to its adhesive properties, it also acts as a co-stimulatory molecule on T and NK cells. It is a specific marker for T cells and NK cells.

Costimulation

The concept that in order to become activated a T cell must receive costimulatory signals in addition to TCR signals. TCR/MHC presentation without this also will result in anergy or limited expansion and apoptotic death of the T-cell.

Cross presentation

The phenomenon whereby APC, while unable to be infected for some reason, can take up extracellular viral antigens by phagocytosis or endocytosis and process/present via the MHC class I pathway for presentation to CD8+ T cells. This is triggered by type I IFN and only with inflammation.

CD8 T cell activation

These cells require higher levels of B7 costimulation in order to become activated. Generally, only dendritic cells express enough B7 to activate them directly. In many immune responses CD4+ T cells assist in the activation of this cell. Effector CD4 can stimulate APC to express sufficient amounts of B7 to activate. Naive CD4 T cells can produce IL-2 that binds to high affinity IL-2 receptors on this cell.

X-linked SCID (Severe combined immunodeficiency)

This disease is caused by absence of expression of the IL-2Rγ chain. Consequently, there is no clonal expansion of antigen-activated T cells. *can't make T cells or B cells*

LFA-3

This is a cell adhesion molecule expressed on Antigen Presenting Cells (APC), particularly macrophages. It binds to CD2 (LFA-2) on T cells and is important in strengthening the adhesion between the T cells and Professional Antigen Presenting Cells. This adhesion occurs as part of the transitory initial encounters between T cells and Antigen Presenting Cells before T cell activation, when T cells are roaming the lymph nodes looking at the surface of APCs for peptide: MHC complexes the T-cell receptors are reactive to.

IL-2R (IL-2 receptor)

This is a high affinity interleukin receptor comprised of alpha, beta and gamma chains. This is not expressed by resting T cells but is induced during T cell activation (TCR-MHC interaction turns on expression of α chain).

IL-2 (Interleukin-2)

This is a secreted T cell growth factor that drives the clonal expansion of antigen-activated T cells. It induces T cell proliferation through binding to cell surface high affinity IL receptors, which are only expressed during T cell activation.

DC (Dendritic Cell)

This is the principal APC that take up antigens at sites of infection (MHC II - endocytosis of extracellular antigen -> processing; or MHC I with viruses) and activate T cells at the induction phase of the immune response. Two types: 1) lymphoid, which are found in T cell areas of secondary lymphoid organs, or 2) immature, which are located in many other tissues such as skin. Note: Infection increases expression of MHC I/II and B7 on its surface. Then it migrates through afferent lymphatic vessels to lymph nodes to present antigen to T cells.

Cortical sinuses and Efferent lymphatics

This is where T cells exit lymph nodes. If specific antigen is encountered, T cells are activated and exit is delayed for several days. Notes: T cells are constantly recirculating between secondary lymphoid organs and blood

HEV (High Endothelial Venule)

This the way through which T cells enter lymph nodes. Notes: T cells are constantly recirculating between secondary lymphoid organs and blood

APC (antigen presenting cell)

Within lymphoid organs, T cells make transitory contacts with these cells, which include dendritic cells, macrophages, etc. Initial adhesion is weak - however, if specific antigen is encountered the avidity of the T cell LFA-1 for ICAM is increased. This weak adhesion is helpful for T Cells to "scan" many of these cells for the right antigen.

Effector T cells

activated T cells that have recently encountered MHC-peptide in the periphery - upon recognition of MHC-peptide they execute their action function.

FasL (Fas Ligand )

binds the Fas death receptor, and starts signaling cascade that results in apoptosis.

Fas

death receptor on the surface of cells that leads to programmed cell death (apoptosis). Forms the death-inducing signaling complex (DISC) upon ligand binding that activates FADD -> caspase 8 -> caspase 3 -> apoptosis.

Memory T cells

resting T cells that have encountered MHC-peptide in the periphery - they are activated quickly upon recognition of MHC-peptide

Naïve T cells

resting T cells that have not previously encountered cognate MHC-peptide in the periphery.

AP1 (Activator Protein-1)

transcription factor involved in T cell activation

NFAT (Nuclear Factor of Activated T cells)

transcription factor involved in T cell activation

NFκB (Nuclear Factor kappa-B)

transcription factor involved in T cell activation

CTLA-4

A CD28-related T cell surface receptor that inhibits T cell activation. It is expressed during clonal expansion of activated T cells. It binds to B7 with higher affinity than CD28 and *blocks T cell costimulation*. Thus, it is an important negative regulator of T cell activation.

CCR7

A T cell chemokine receptor involved in T cell attraction to lymph nodes

CD28

A T cell surface costimulatory receptor. It binds to the B7 costimulatory molecule that is expressed only on professional APCs. It contains anti-apoptotic signals that allows TCR to be stimulated by MHC presented antigens and undergo clonal expansion. It also manages contraction of T-cells after the infection is cleared by reducing the costimulatory signal.

S1P (sphingosine 1 phosphate)

A lipid that functions as a chemoattractant for T cells. Present at high concentrations in blood and lymph.

CD69

A molecule that is expressed on the surface of activated T cell that controls responsiveness to S1P. T cell activation in lymph node results in its expression which internalizes S1P1 (now T cell can't exit).

ALPS (Autoimmune Lymphoproliferative Syndrome)

An autoimmune disease caused by defective Fas-mediated apoptosis of T lymphocytes. *STOPS T CELL DEATH MECHANISM*. Absence of negative regulation of T cell clonal expansion leads to too many T cells -> autoimmune problems, like lupus.

IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked)

An autoimmune disease in humans caused by an *absence of Treg*. Autoimmune features, particularly diabetes Early mortality Patients lack functional FoxP3 and hence Treg

Immunological synapse

At the outset of T cell activation, the TCR,CD4/CD8 co-receptors, CD28 and adhesion molecules cluster to one pole of the cell that apposes clustered specific MHC/peptide complexes on the APC. This structure that forms in the area of close contact between a T cell and an APC displaying the TCR specific antigen.