Lec 39: Cell Interaction Molecules

Question 1

Describe the major function(s) and pattern of expression of the following molecule: B cell receptor

Answer 1

BCR: Expressed on B cells, the BCR is a form of antibody that is surface bound

Question 2

Describe the major function(s) and pattern of expression of the following molecule: TCR

Answer 2

TCR: - one antigen binding site - TCR is obligatorily associated with the CD3 complex - CD3 functions as the signal transducing subunit of the TCR - Cytoplasmic side of the CD3 complex contains immunoreceptor tyrosine-based activation motifs (ITAMs)

Question 3

Describe the major function(s) and pattern of expression of the following molecule: CD2

Answer 3

CD2: Protein expressed on T-cells that binds to LFA-3 on APCs during immunological synapse. Involved in signal transduction and increased adhesion to the APC (Antigen presenting cell)

Question 4

Describe the major function(s) and pattern of expression of the following molecule: CD3

Answer 4

CD3: Protein specific to T cells, strongly associated with the TCR and involved in signal transduction upon TCR activation

Question 5

Describe the major function(s) and pattern of expression of the following molecule: CD4

Answer 5

CD4: Helper T-cell, MHCII restricted, TCR binds MHCII, CD4 binds with beta-2 non-polymorphic region of MHCII

Question 6

Describe the major function(s) and pattern of expression of the following molecule: CD8

Answer 6

CD8: Cytotoxic T-cells, MHCI restricted, TCR binds MHCI, CD8 binds alpha-3 non-polymorphic region of MHCI

Question 7

Describe the major function(s) and pattern of expression of the following molecule: CD28

Answer 7

CD28: Costimulation protein in activation of a Tcell during immunological synapse. Required to bind to B7-1/B7-2 on professional APC in order to activate naive T cell and induce proliferation

Question 8

Describe the major function(s) and pattern of expression of the following molecule: L-selectin

Answer 8

Adhesion molecules - L-selectin: Naïve T cells and EC of HEV Selectin on t-cell interacts with Sialyl lewis X of HEV Vascular addressins - bear carbohydrate ligands that are recognized by L-Selectin CD34 GlyCAM-1

Question 9

Describe the major function(s) and pattern of expression of the following molecule: LFA-1

Answer 9

LFA-1 - integrins expressed on T cells; LFA-1:ICAM-1 most important in stabilization Interaction between T cells and APCs LFA-1 on t cell with ICAM 1 on antigen presenting cell

Question 10

Describe the major function(s) and pattern of expression of the following molecule: B7

Answer 10

Only expressed on professional APCs Dendritic cells Macrophages B cells Binds CD28 and CTLA-4

Question 11

Describe the major function(s) and pattern of expression of the following molecule: CTLA-4

Answer 11

CTLA-4 Induced by activation of Tcell receptor Binds same ligands CD28, but with higher affinity Delivers negative signal to Tcell Modulates Tcell immune response

Question 12

Describe the major function(s) and pattern of expression of the following molecule: CD40 and CD40L

Answer 12

CD40 - Bcell costimulation Induced as a consequence of antigen recognition/BCR engagement -> Bcell prolif and diff CD40L Present on Tcell Binds CD40 -> cytokine production

Question 13

Explain regulation of IL-2R affinity by Tcell activation:

Answer 13

1. Naive Tcell activated by “professional” APC by binding MHC complex + costimulator (CD28/B7 interaction) 2. Activated Tcell releases IL-2 as IL-2R begins to express the alpha chain forming a high-affinity IL-2R complex (alpha+beta+gamma chains) 3. IL-2 binding to activated IL-2R induces Tcell proliferation

Question 14

What is the difference between low-affinity IL-2R and high-affinity IL-2R?

Answer 14

The IL-2R alpha chain. Low affinity = beta+gamma chains High affinity = alpha+beta+gamma chains

Question 15

What immunosuppressive drug can be used to inhibit IL-2 Signaling and how?

Answer 15

Rapamycin - blocks IL-2R signaling to p70(S6) kinase, which inhibits T cell proliferation. Used during organ transplants to prevent rejection.

Question 16

Define costimulation

Answer 16

Costimulation- seconday signal required to initiate a full response. Partial signal will not elicit full response Anergy - turning off t cells in the periphery that do not have co-stimulatory signal Recognizes antigen, however no B7 signal from APC, thus no 2nd signal

Question 17

Describe the mechanism of “inside-out” signaling to activate LFA-1 adhesion.

Answer 17

ICAM-1 on APC binds low affinity LFA-1 on T cell Binding triggers APC to release chemokine -> clustering of LFA-1 and increased affinity of integrins Strong t cell:APC adhesion -> tcell response

Question 18

Describe the organization and function of the immunological synapse IS, naming the critical pairs of cell interaction molecules that are components of the IS

Answer 18

Bulls eye patterns on SMAC, clusters of similar receptors Initial clustering after antigen helps signal transduction and subsequent diff Extreme reorganization Adhesion molecules pushed to the outside holding cells in place but facilitating signaling Forms stable contacts and establishes polarity for directional cytokine secretion Antigen signals to tcell cause re-positioning of secretory apparatus towards APC or target * CD4+ - allows cytokines to be delivered to APC * CD8+ allows cytolytic enzymes to be directed at target cell

Question 19

Define cytokine, and describe the general features of cytokine secretion and action.

Answer 19

Small secreted molecules that have effects across many cell types Autocrine: IL-2 Paracrine: Chemokine recruitment and Chemotaxis Endocrine: IL-1, 6, and TNF-a in shock Effects are highly dependent upon concentration Example TNF: Low -> local inflammation Medium -> systemic effects High -> septic shock Tightly regulated by transcriptional and mRNA level. Single cytokine may target many different cell types. INF-y vs IL-10 in macrophages

Question 20

Describe, in detail, the function of IL-2 and the regulation of expression of the IL-2 receptor

Answer 20

• Regulation of IL-2 receptor affinity by t cell activation
  
  • T cell activation by antigen + costimulator
  • Secretion of IL2
  • Expression of IL2…..
• Signals from high affinity IL-2 receptor induces T cell proliferation
  
  • Naïve t cell express low affinity
  • Activated t cell express high affinity
• Rapamycin blocks cytokine signaling and T cell proliferation thereby dampening T-cell response and extends window of organ transplant tolerance

Question 21

Explain the significance of the 3 chain structure of the IL-2 receptor. Define autocrine

Answer 21

• When the 3 subunits come together, the affinity for IL2 increases 100x
• This occurs when activated by antigen
  
  • Provides a mechanism to specifically target activated cells and deliver IL2
  • Rapamycin blocks IL2 receptor signaling and dampens Tcell response to increase window for transplant

Question 22

What is integrin activation mediated by GCPR?

Answer 22

Chemoattractant binds GCPR -> signal cascade -> integrins change to high affinity conformation.