1. Biology of T cells
The individual has an enormous number of different T cells. Each T cell bears a unique, clonally distributed receptor for antigen, known as the T-cell receptor. The same rearrangement strategies and recombinase machinery are used to generate a repertoire of T cells with different TCRs as are used by B cells to generate Ig diversity.
On the majority of human and mouse T cells, the TCR is a two-chain transmembrane molecule, . The TCR is made up of V and C regions, analogous to those of Ig molecules. The extracellular portion of the TCR resembles the Fab region of an antibody.
An  TCR interacts with a peptide bound to an MHC molecule on the surface of a host cell.

4. 4. Co-receptor molecules are associated with the  TCR
4. Co-receptor molecules are associated with the  TCR. On mature T cells, the co-receptor is either CD4 or CD8, dividing T cells into two subsets, either  CD4+ or αβ CD8+. The function of these co-receptor molecules is to (1) bind MHC molecules on an antigen-presenting cell, (2) tighten the adherence between the T cell and antigen presenting cell, and (3) play a role in signal transduction after activation of the TCR.
5. The antigen-binding  chains of the TCR are expressed on the surface of the T cell in a multimolecular complex (the TCR complex) in association with CD3 and  polypeptides, which act as a signal transduction unit after antigen binding to .
6. The T cell also expresses molecules on its surface with important costimulatory, adhesion, and/or signal transduction properties. These include

5. 7. CD 28, CTLA-4(CD152), the integrins LFA-1 (CD11aCD18), and VLA-4 (CD49d,CD29), and CD2; and molecules, involved in homing to different tissues.
8. A different two-chain structure, , is the TCR on a minor population of human and mouse T cells.  is also expressed on the surface of the cell in association with CD3 and  . + T cells do not express CD4 but some express CD8. the functions of + T cells are not as well understood as those of + T cells.
9. The genes coding for the ,  and  chains of the TCR show allelic exclusion__that is, genes from only one chromosome are used to synthesize the polypeptide chain. TCR  genes do not show allelic exclusion.
10. The TCR is initially expressed on the surface of developing T cells during differentiation in the thymus. The divergent development of T cells using  as their receptor from those using  as their receptor occurs early in the differentiation pathway in the thymus.

6. 11. TCR+CD4+CD8+ thymocytes (double positive) cells undergo thymic selection, mediated by interactions of the TCR and co-receptor molecules on the developing T cell with MHC molecules and peptides expressed by the thymic nonlymphoid cells. Positive selection on cortical epithelial cells educates the developing T cell: As a mature cell, it responds to antigen only when presented by a cell that expresses the same MHC molecules that the T cell interacted with during differentiation in the thymus (MHC restriction of the T-cell response). Negative selection on dendritic cells at the junction of the thymic cortex and medulla removes T cells with potential reactivity to self molecules, ensuring self-tolerance. Thus TCR+ T cells that emerge from the thymus are self-MHC restricted and self-tolerant.
12. TCR+CD4+ and TCR+CD8+ T cells that survive negative selection, together with + T cells, leave the thymus. These cells constitute the repertoire of peripheral T cells in blood, secondary lymphoid organs, and tissues that respond to non-self (foreign) antigen.

7. The T cell Receptor Complex
TCR.
CD3 ((expressed exclusively on T cells "Marker")).
Two zeta chains (CD247).
CD3 & zeta polypeptide do not bind Ag, they are signal transduction molecules activated after Ag-binding to the TCR analogous to Ig and Ig molecules associated with BCR.
After Ag binds to the  and  chains of the TCR, the immunoreceptor tyrosine-based activation motif (ITAM) of CD3, and zeta chains play important roles in the early phases of T cell activation.

8. TCR and Ig and other molecules expressed at the cell surface have evolved from a common ancestral gene. These genes belong to the Ig gene superfamily.

9. TCR VS Ig
TCR is monovalent and resembles the monovalent Fab fragment of Ig.
TCR has rigid conformation due to extensive interactions between the domains of each TCR. While Ig molecule is flexible "four chains with hinge region and two Ag-binding sites".
TCR interacts with small fragments of proteins that are expressed on the surface of a host cell which are associated with MHC molecules "Fig 8.2".
While Ig molecules recognize variety of structures and shapes of Ags.
Unlike Ig, the TCR does not exist in a specifically secreted form and is not secreted as a consequence of T cell activation.
No change in the TCR during the response to Ag. While Ig molecules undergo somatic hypermutation and class switching.

11. LCA; Leukocyte common Ag, CTL; Cytotoxic T lymphocytes,
VLA;Very Late Ag, CTLA; Cytotoxic T Lymphocyte Ag,
LFA; Lymphocyte Functional Ag.
Co-receptor molecules
CD4 or CD8, immature T cells differentiating in the thymus express both CD4 and CD8.
CD4 binds selectively to MHC class II.
CD8 binds selectively to MHC class I.
CD4 and CD8 act as adhesion molecules in T cell interactions with APC, they help tighten the binding of T cells to APCs "Fig 8.3".
CD4 and CD8 are involved in signal transduction after Ag-binding to the TCR. The intracellular portions of CD4 and CD8 are linked to enzymes, known as tyrosine kinase, which are important early components of the T cell activation pathway. The ratio of CD4:CD8 is 2:1.

12. Costimulatory Ligands
The interaction of B7 with CD28 expressed on the mature T cell provides a co-stimulatory or second signal for T cell activation.
The co-stimulator interaction is required in addition to the interaction of peptide-MHC with the TCR to activate naïve T cells ((i.e. T cells that have not previously encountered Ag)).
Activated T cells also express a molecule closely related to CD28 known as CD152 "CTLA-4" that interacts with B7 molecules to impart a negative signal to the activated T cell.
All mature T cells express CD2 which also has adhesive and signal transduction properties in addition to CD4 and CD8.

13. Cells and APC such as macrophages and dendritic cells. Homing:
CD2, CD4, CD8 are expressed exclusively on T cells.
Integrins (LFA-1, VLA-4).
LFA-1 on T cells interacts with several ligands including ICAM-1(CD54) on endothelial
Cells and APC such as macrophages and dendritic cells.
Homing:
Homing is mediated by binding of CD62L "L-selectin" expressed on naïve T cell surface to glycoprotein molecules known as addressins expressed on cells in a specialized region of the vascular endothelium at the boundry of the nodes.

14. T cell Differentiation in the Thymus
The developing T lymphocytes "thymocytes" interact with nonlymphoid stromal cells of the thymus e.g. cortical epithelial cells and dendritic cells found at the junction of the cortex and medulla.
The nonlymphoid cells provide critical cell surface interactions required for the development of maturing T cells, they also produce IL-7 which induces proliferation of T & B cells.
The ratio of T:B cells is 3:1
T cells differentiate under the influence of thymic hormones" thymosine and thymopoiten" into T cell subpopulations.

15. Thymic Selection (A) Positive selection
TCR of double + thymocytes interact with MHC of cortical epithelial cells which results in survival and differentiation of ++ cells.
Double + cells that do not make this critical interaction undergo apoptosis.
Positive selection results in down regulation of RAG-1 & RAG-2 gene expression thus halting further gene rearrangement.
The developing  TCR becomes educated to MHC molecules on thymic epithelial cells, thus it will respond to Ag when bound to MHC.
MHC molecules expressed in a persons' thymus and that educate his or her developing T cells are referred to as self-MHC for that person.
All other types of MHC molecules are non-self. This is the origin of the phenomenon known as MHC restriction or self-MHC restriction which is central to T cell responses.

16. Negative Selection
The recombination events involved in TCR generation are more or less random. T cells expressing TCRs specific for both foreign and self Ags can develop in the thymus and survive positive selection.
If T cells with strong reactivity to self components leave the thymus and interact with Ags in tissues could result in autoimmune responses.
To prevent this, the double + cell undergoes selection step known as negative selection.
Negative selection takes place when double + cells interact with dendritic cells at the corticomedullary junction. The critical interactions are between the TCR CD4 and CD8 expressed on double + cell and the MHC molecules expressed on dendritic cell.

17. Double + cell interact with MHC and peptide expressed on the dendritic cell surface.
A T cell expressing TCR that reacts with too high an affinity to the combination of MHC and peptide is deleted by apoptosis. Thus negative selection removes T cells expressing TCRs with high (or strong) reactivity to self component.
Double + cells that survive negative selection downregulate expression of either CD4 or CD8. this results in the development of either CD4+ CD8- CD4- CD8+ T cells. They leave the thymus.
These cells are self-MHC restricted i.e. they interact with peptides derived from non-self Ags only.
These cells are self-tolerant they do not respond to self components.

18. Role of AIRE Gene Product in Negative Selection
How do we develop self-tolerance to molecules normally found outside the
Thymus?
Studies indicate that at least some self-molecules normally synthesized by
Tissues outside the thymus, including insulin, thyroglobulin and myelin basic
Protein are expressed by epithelial cells in the thymic medulla.
These studies suggest that the medullary epithelial cells and more specifically
the product of the autoimmune regulator or AIRE gene expressed by these cells
also play a role in negative selection.

19. The AIRE gene product codes for a protein that at least partly controls the
expression of self molecules in thymic medullary epithelial cells.
If the AIRE gene product is lacking, deletion of autoreactive T lymphocytes
is impaired and autoimmune responses develop such as autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome(APECED),
in which multiple endocrine organs are targeted.
N.B Thymus involution in adults does not affect T cell production . Two explanations are made:
1- Remnants of the thymus produces T cells.
2- Extra site takes over.
However, if thymus is removed , T cells are made somewhere, this is in favor of explanation number 2.

20. *Some children are born with a thymus that fails to develop correctly
In utero (DiGeorge Syndrome).
*Mice in which the thymus does not develop are called nude mice
Because they also lack hair.
*In both cases mature T cells do not develop and T-cell responses
Are defective.

22. Comparison of T cells and B cells
Feature T cells B cells
________________________________________________________
Antigen receptors on surface Yes Yes
Recognition only of processed peptides plus MHC Yes No
No requirement for Ag presentation by MHC No Yes
IgM on surface No Yes
CD3 proteins on surface Yes No
Clonal expansion after cotact with specific Ag Yes Yes
Immunoglobulin synthesis No Yes
Regulator of Ab synthesis Yes No
IL-2,IL-4,IL-5,and gamma interferon synthesis Yes No
Effector of cell-mediated immunity Yes No
Maturation in thymus Yes No
Maturation in bone marrow No Yes

23. N:B NK cells and NKT cells develop in the thymus.
Treg cells are a subset of CD4+ T cells, they express CD25,they play a role in inhibiting responses to both self and foreign Ags.
Both CD4+ and CD8+ T cells leave the thymus to blood and 2ry lymphoid organs, after Ag activation they differentiate into effector cells, some activated T cells become memory CD4+ or CD8+ cells.