Lymphocyte Interactions

1. Lymphocyte Interactions • Both the activation and functions of lymphocytes require them to interact with each other and with other cell types. • The opportunities for lymphocyte interactions are maximized by the recirculation of lymphocytes through out the body and by their homing to secondary lymphoid tissues.

2. The Surface molecules of The Mature B Cell • Antigen-binding molecules：surface immunoglobulin（sIg，前章節已介紹）。 • 於成熟B細胞才表現，可利用偵測此分子而將B細胞由混合淋巴球細胞群中純化出。 • Signal transduction molecules： 1. Igα（CD79a）、Igβ（CD79b） • 進行Signal transduction：the kinases associated with Igαand Igβ phosphorylate several cellular proteins. Phosphorylation of these proteins leads to the transcription of different genes in the B cell and to B-cell activation。 2. Additional signal transduction molecules：CD19、CD20、CD21 • To play coreceptor role for B cell receptor（immunoglobulin）。 • To play a similar signal transduction role as the CD3 complex in T cell。

3. The Surface molecules of The Mature B Cell • CD40：involved in isotype switching • The molecule accepts the soluble factors（cytokines）released by T cell。 • Antigen presentation molecule：MHC class II molecules 1. MHC class II molecule expression is found on all cells of the B-cell lineage, starting with the pre-B cell。 2. B-cell expression of MHC class II molecules is constitutive（always expressed）。 3. The expression of MHC class II molecules can be further increased by exposure to certain cytokines。 • Costimulatory molecule：B7（B7-1（CD80）、B7-2（CD86））

4. The Surface molecules of The Mature B Cell 1. To interact with surface molecules on T cell to send crucial positive signal to the T cell during antigen-specific stimulation。 2. Resting B cells are poor APCs and express low levels of costimuatory molecules。 3. Activated B cells express high levels of costimuatory molecules and very efficient APCs。 • Fc receptor（FcR）：CD32 • CD32 is believed to play a role in "antibody feedback," the inactivation of B cell by antigen on the presence of antibody。 • Complement receptor：CD21(CR2), CD35 (CR1) • CD21 involved in B-cell activation and is a receptor for a complement component, C3d。 • CD35 involved in B-cell activation and is a receptor for a complement component, C3b。 • Cytokine receptor

5. Overview of surface molecules of B cell

6. (55 kDa, glycoprotein) (30-38 kDa, glycoprotein) Or αα homodimer The Surface molecules of The Mature T Cell • TCR complex（含TCR、CD3 complex，前章節已介紹）。 • Co-receptor（accessory）molecules：CD4、CD8 1. Co-receptor molecule expression divides the αβ+ T cell population into two major subsets。 2. To act as adhesion molecular that help to tighten the binding of T cell to antigen-presenting cells。 3. They also act as signal transduction molecules, sending signals into T cell。

7. The Surface molecules of The Mature T Cell • CD45 1. It is a large（180-220 kDa）cell surface molecule expressed by all leukocytes, including T cell。 2. Its cytoplasmic domain has tyrosine phosphatase activity. 3. T cells that lack CD45R cannot respond to antigen , even though they express normal levels of TCR. • Molecules interacting with CD40：CD40L（CD40 ligand, gp39） 1. It is a 30-39 kDa glycoprotein expressed on actived T cells。 2. It interact with CD40 on B cell surface to induce antibody class switch。 • Adhesion molecule：CD2、LFA-1（leukocyte function associated antigen-1，CD11aCD18） 1. CD2 plays a role in adhesion to enhance the bindung of T cells to other cells, and its ligand is CD58（LFA-3）found on many cells’ surface。

8. The Surface molecules of The Mature T Cell 2. CD2 is the one of the first T-cell-specific molecules expressed, and it is expressed throughout the life of the T cell。 3. LFA-1 bind to CD58（intercellular adhesion molecule-1，ICAM-1）on other cells to enhance the bindung of T cells to other cells。 • Molecules interacting with costimulatory molecule：CD28、CTLA-4

9. The Surface molecules of The Mature T Cell 1. They involve the interaction of molecules on the APC and T cell surface。 2. CD28, a transmenbrane protein and a member of Ig supergene family, interacts with B7 on the surface of APC, and this interaction appears to be crucial in generation of IL-2 following the stimulation of resting, unprimed T cells。 3. CTLA-4 has the same interaction as CD28, but this interaction may be a negative signal to activate T cell, serving to turn off the production of IL-2 and thus limiting the extent of the immune response。

10. Overview of surface molecules of T cell

11. The Surface molecules of The Antigen Presenting Cell • MHC molecules：Class I、Class II • Costimulatory molecule：B7（B7-1（CD80）、B7-2（CD86）） • Adhesion molecule：CD58（LFA-3）、CD54（intercellular adhesion molecule-1，ICAM-1）

13. CD4+/CD8+T-APC Cell Interaction • In CD4+ T cells, TCR interacts with the peptide-MHC class II complex（antigen-specific activation）, and this recognition is crucial in initiating the series of events that results in T cell activation。 • The interaction between TCR and peptide-MHC class II（class I）complex is increased by CD4（CD8）on T cell surface. • Adhesion pairs, such as CD2/ CD58（LFA-3）、LFA-1 /ICAM-1, further enhance T-cell-APC interaction。 • Costimulatory pair, such as CD28/B7, is required to complete the process of T-cell activation（to be vital in activating unprimed, resting T cell）。 • Interaction of the costimulatory pairs is crucial for production of the IL-2 by T cells。 • Not all MHC class II+ APCs are effective, that is, costimulatory molecule expression correlates with their relative effectiveness as APC。

14.    Affinity of interaction: TCR  + adhesion molecules  + growth factor receptors (costimulatory molecule) 

15.    Affinity of interaction: TCR  + adhesion molecules  + growth factor receptors (costimulatory molecule) 

16. B-T Cell Interaction • Costimulatory pair, such as CD28/B7 Induction of B7 expression enhances the ability of the B cell to act as an effective antigen-presenting cell。 • Adhesion pairs, such as CD2/ CD58（LFA-3）、LFA-1 /ICAM-1, further strengthen T-B cell interaction。 • CD40-CD40L binding promotes B cell proliferation and is required for the B cell to switch the class of antibody that it can synthesis（the absence of this interaction, only IgM is made）。 • Cytokine receptor-T cell derived cytokines binding also is required for the B cell to switch the class of antibody。 1. IL-4  B cell will switch to produced IgE。 2. IFN-γ B cell will switch to produced IgG subtypes。

17. Interaction between B and T Cell

18. B-T Cell Cooperation in Antibody Production • Thymus-dependent（TD）antigens enhance CD4+ T cell to cooperate with B cells in the production of antibody • The production of antibody to thymus-dependent antigen requires that both B and T cells be activated and interact。 1. Many of the cytokines secreted by the activated T cell to activate B cells。 2. The phenomenon of T-B cell cooperativity is known as linked recognition。 3. In primary response, T-cell activation results in IL-2 synthesis, which appears to be necessary for B-cell activation and proliferation and results in B-cell secretion of IgM；in secondary response, IgG, IgA, and IgE antibodies are produced。

20. No T-cell Help in Antibody Production • The thymus-independent（TI）antigen do not use T-cell help, do not induce memory B cell and B cell cannot switch from IgM isotype。 • The thymus-independent（TI）antigens’ commom properties： （1）are large polymeric molecules with multiple, repeating, antigenic determinants （2）have some poorly defined mitogenic properties（polyclonal activators）: at high concentrations they are able to activate B-cell clones to poliferate and to produce antibody。

22. Activation of Help T Lymphocytes • Help T cell activation occurs early in an immune response, and requires 2 signal： 1. Signal I is provided by binding of TCR to peptide-MHC complex and is transmitted through the CD3 complex。 2. Signal II is costimulatory signal。 • The signals induce help T cell to begin secreting IL-2 and also to begin expressing specific high-affinity IL-2 receptors on its surface。

23. Activation of Help T Lymphocytes 1. IL-2 has a very short half-life outside the cell and so act only over extremely short distances。 2. IL-2 exerts its greatest effects on the cell from which it is secreted, called as autocrine effect。That is, T cell will not begin to proliferate in the absence of IL-2 or if its own surface IL-2 receptors are blocked。 3. The IL-2 can also act on cell in immediate vicinity, called as paracrine effect

25. Activation of Help T Lymphocytes • APC may begin to release IL-1 to act primarily in an autocrinemanner on itself。 • IL-1 function： （1）To increase the expression of MHC class II and various adhesion molecules on APCs。 （2）To strenghten binding of TH cell and APCs。 （3）To enhance antigen presentation of APCs。 （4）To be in paracrine manner on the TH cell to promote IL-2 secretion and IL-2 receptor expression。 （5）To potentiate the TH cell poliferative response。 • There are TNF（tumor necrosis factor）and IL-6, produced by macrophages, that can mimic with IL-1 activity。

27. Activation of TC Cell by TH Cell • Activation of TC cell • Two signals are necessary for TC cell activation： （1）Signal I alone induces high-affinity IL-2 receptors on the TC cell。 （2）Signal II is finished by IL-2 secreted from a nearby activated TH cell。 • On receiving both signals, the activated TC cell acquires cytotoxic activity（by releasing specific toxins or inducing target cell suicide）

28. Activation of B Cell by TH Cell • Activation of B cell • By direct contact with TH cell。 • Cytokine activation：helper cell factor：IL-2、IL-4、IL-5。

29. The induction of immune responses by cellular interaction