Quiz/Prelim 3 Flashcards
The Primary B Cell Response
- Mature naive B cells patrol follicles for antigen that binds their BCR and then they activate
- Some activated B cells differentiate and create IgM
- Some improve their BCR, then differentiate and create 2nd wave of IgG, IgE, IgA or memory B cells
How do naive B cells find Ag in lymph nodes?
One way to arrive is via HEV. Naive B cells express L-selectin (like naive T cells) and CXCR5 to migrate to B cell areas that hold CXCL13
What do follicles in the secondary lymphoid tissue do?
Collect Antigen
Antigens that flow to the lymphatics
- Pathogens and their antigens are tagged with innate C3b all the time. C3b is continually broken down into C3d
- Macrophages and follicular dendritic cells (FDC) use complement receptor 2 to capture C3d-tagged antigen
How do naive B cells move from lymph node to lymph node?
Naive B cells that leave one lymph node will travel via lymphatic vessels to the next lymph node and enter it via the afferent lymphatic vessel as shown here
What are the two ways B cells can enter the lymph node?
- Through the HEV
- Through the afferent lymphatic vessel
Follicular dendritic cells (FDCs)
- The dendrites hold antigen complexes that are tagged with complement or antibody
- They hold the antigen in the B cell area, and B cell follicles form around them
- FDC are NOT immune derived dendritic cells. They do not present antigen to activate T cells
- FDC don’t phagocytose and process antigens. They simply hold it. They don’t provide co-stimulatory B7
What does conventional B2 cell need to activate?
- Need AgR/coreceptor + co-stimulation from CD4 Tfh (T-dependent B cell)
What does B-1 cell need to activate?
- A multivalent antigen clusters BCR + TLR activation signal
What is signal 1 for B-2 cell activation?
- Antigenic signal 1 means that the BCR is bound to an intact antigen and the coreceptor complex which is mainly just referred to as CD19 (but includes CD21 and CD81)
What is signal 2 for B-2 activation?
CD40L from a Tfh cell
What is signal 1 for B-1 cell to activate?
- Antigenic signal 1 meaning an intact antigen and CD19
What is signal 2 for B-1 cell to activate?
- Co-stimulatory Signal 2 - pattern recognition receptor (like a TLR)
What does the BCR complex bring?
- Iga and IgB, ITAMS, and tyrosine kinases (Blk, Lyn, Fyn)
What does the coreceptor complex bring?
- CD19 to recruit and activate PI3
- Complement Receptor 2 (CR2) to bring co-receptor complex close to BCR by binding plentiful complement tags (C3dg, C3d)
- CD81 to bring co-receptor receptor to the surface
Blk, Fyn, Lyn
Src-family tyrosine kinases of B cells that act like Lck tyrosine kinase of T cell
What do the interactions between BCR complex and co-receptor complex lead to?
It leads to the creation of PLC-y activation and the production of second messengers, DAG and IP3
Phosphlipase C-y
Key enzyme in intracellular signaling paths that breaks cell membrane phospholipids into the powerful second messengers DAG and IP3
What is the difference between B cell and T cell signaling activation in terms of co-stimulatories?
- For B-2 cells, antigenic signal 1 (and its coreceptors) is enough to activate PLC-y and second messengers (DAG and IP3) . B-2 cells also don’t need for both of the signals to be simultaneous
- For aB T cells, antigenic signal 1 and co-stimulatory signal 2 are required to make a scaffold for activation of PLC-y and second messengers (DAG and IP3)
How do B cells get help from CD4 Tfh
B-2 cells present peptides from the Ag via MHC II at the edge of the T cell area. Any activating pre-Tfh migrate towards B cell area to meet the B-2 cells
Do B cells and Tfh recognize the same epitope?
No, they recognize different epitopes of the same antigen. This is called linked recognition
The B and Tfh have formed a cognate pair via an immunological synapse (adhesion molecule not shown)
How do partially activated B and pre-Tfh meet in lymphoid tissues?
- Antigen-activated (partially activated) B-2 cells use CCR7 to migrate towards CCL19 and CCL21 in T-cell areas
- Antigen-activated pre-Tfh use CXCR5 to migrate towards CXCL13 in B areas
- They meet at the boundary. If they recognize epitopes of the same antigen, they form an immune synapse and finish activating each other
How do partially activated B and pre-Tfh activate one another once they meet?
- remember the second function of BCR is to endocytose antigen in order to present it on MHC II***
- A pre-Tfh that recognizes peptide from the endocytosed antigen presented by the activating B cell will form an immunological synapse with the B cell (linked recognition)
- Pre-Tfh delivers to B: signal 2 co-stimulation (CD40L) and Signal 3 for proliferation of B and to itself (IL-21, IL-6)
Which signals do Tfh give B-2 cells?
- Gives them signal 2 and signal 3
Linked recognition
A helper T cell and a B cell recognize different epitopes from the same antigen. The B cell recognizes a native epitope with its BCR; the T helper cell recognizes a peptide epitope from the same antigen which is presented on MHC II by the B cell
How do B cells and Tfh finish activating each other?
- They activate each other via an immune synapse
- B cell supplies co-stimulatory molecule, ICOS-L to the cognate pre-Tfh
- Tfh locks in the Bcl-6 defining transcription factor and finishes differentiation
- Cytokines IL-21 and IL-6 drive the pair to proliferate - many copies of both B and T are made. Many daughter B cells differentiate into plasmablasts.
ICOS Ligand
A co-stimulatory molecule of the B7 family expressed by antigen-activated B cells. Provides additional co-stimulation to pre-Tfh cells in order to express the defining transcription factor, Bcl-6, stably and differentiate into Tfh effectors
What stage of a B cell can express ICOS-L
Antigen-activated B cells
Once a B cell gets activated, what happens to it?
- Some immediately differentiate into plasmablasts or short-lived PC (plasma cells) for IgM that goes into the bloodstream
- Some travel as cognate pair ( B and T cell still together) back to follicle and start a germinal center for improving and a second wave of Ab. IgG, IgE, and/or IgA
Primary IgM (antibody) response
First antibody to be made in a (primary) B cell response to a threat that had never been encountered. Plasmablast secrete BCR as antibody. IgM specializes in opsonizing threats and activating complement defenses
Primary follicle*
Place where naive B cells are activated
Germinal center (aka secondary follicle)
Place where activated B-2 cells improve receptor affinity, switch isotypes and differentiate into memory B cells or plasma cells
But isn’t the germinal center the same as the primary follicle?
When the cognate pairs return back to the primary follicle to proliferate and mutate BCR genes, the expansion of them is so great that the primary follicle turns into the germinal center
Similarities btw B cell and T cell activation
- Same routes entry and exit of lymphoid tissue.Antigen and naive B cells meet here
- Require 2 activation signals simultaneously, antigen R and co-receptor transmit signal 1. CD40 costimulatory receptor 2 (but the co-receptor is optional for B cells)
- Similar clustering and second messengers
- Clonal proliferation of activating cells (plasmablasts)
- Cytokines give differentiation instructions
Differences btw B cell and T cell activation
- Activate in different areas that hold different forms of antigen
– Intact antigen held by FDC or macrophages for B cells
– Processed antigen presented by cDC for T cells - B-2 cells require cognate Tfh help
– Costimulatory signal is Tfh CD20L for B cell
– B cell needs IL-21 and IL-6 from Tfh for proliferation - Effector B cells are eventually plasma cells secreting Ab
- Effector T cells are CD8+ cytotoxic or CD4+ helper
What is the effector goal of B cells and T cells?
- Effector B cells are eventually plasma cells secreting Ab
- Effector T cells are CD8+ cytotoxic or CD4+ helper
