Lecture 7-12: Adaptive Immunity/B cell/T cell/Lymphoid organs

what is the function of primary lymphoid tissue?

development and education of lymphocytes

what are the primary lymphoid organs?

thymus, bone marrow, Peyer’s patches (ruminants/horses), bursa (birds)

where is the thymus located?

in the cranial mediastinum over the heart

how is the thymus structured?

Dark area, light area

what does the dark area of the thymus contain?

lymphocyte rich cortex

what does the light area of the thymus contain?

thymic medullary epithelium

which cell migrate to the thymus?

lymphoid progenitor cells from the bone marrow migrate to the thymus

what type of lymphocytes do the lymphoid progenitors become in the thymus?

T cells

what is the structure of the bone marrow?

large amount of hematopoietic cells supported by reticular connective tissue, adipocytes, and sinusoidal cappilaries

how is the bursa structured in the bird?

round sac located above cloaca, contains folds of epithelium containing lymphoid follicles

what type of lymphocytes develop in the bone marrow?

B cells

what does education indicate relative to lymphocytes?

training in which B cells and T cells undergo to distinguish self from non-self antigens

what is the importance of the education of lymphocytes?

to avoid hypersensitivity and autoimmunity

what are naive lymphocytes?

lymphocytes that have not encountered specific antigens and been activated

where do naive lymphocytes migrate after development in the primary lymphoid organs?

travel to secondary lymphoid organs

what occurs to lymphocytes when they enter the secondary lymphoid organs?

circulate to encounter antigens and to develop into effector lymphocytes

what is the structure of the BCR?

contains 2 heavy chains, 2 light chains, bond by disulfide bonds

what forms the heavy chains of the BCR?

Fc region

what is the structure of the light chains?

Fab region

what is the function of the Fab region?

antigen binding regions - contain variable regions

what does the Fc region contain?

constant region that determines isotype and primary function of immunoglobulin

how is the TCR structured?

heterodimer of 2 chains with a variable and constant region

what are the possible constant regions?

alpha and beta; gamma and delta

which species contains a large quantity of gamma and delta T cells?

ruminants

what is the driving factor of the formation of diverse and unique BCR and TCR to create the specificity of the immune response?

gene rearrangement

what occurs during gene rearrangment?

random selection of gene segments resulting in genetic diversity of BCR and TCR

where does gene rearrangement occur?

primary lymphoid organs

how are B cells educated?

undergo central tolerance

what are the two fates of self-reactive B cells?

• apoptosis and negative selection

• receptor editing of variable region genes, followed by apoptosis if edit fails

what genes make up the variable region of the T cell?

V - variable gene segment

D - diversity gene segment

J - joining gene segment

what are the genes that are only found in lymphocytes and are involved with cleaving DNA and protecting the dsDNA breaks from repair mechanisms?

RAG1 and RAG2

what are the 3 major steps in T cell development?

rearrangement of TCR genes, positive selection, negative selection

what occurs when TCR genes rearrange?

Αβ and γδ TCRs compete for expression

what occurs if Αβ TCR win?

surface molecules are expressed on developing thymocytes

what occur if γδ TCRs win?

cell leaves thymus

what are the surface receptors on Αβ T cells?

CD3, CD4 and/or CD8

what is the process of positive selection?

• cells become class restricted by recognizing antigens presented on MHC1 or MHC2 molecules of thymic epithelial cells

• cells with TCR that can bind to MHC molecules and antigen are positively selected for; cells lacking undergo apoptosis

what does class restriction lead to?

upregulation of CD8 or CD4 receptors

what happens if a TCR binds to MHC 1 molecule?

upregulation of CD8

what happens if a TCR binds to a MHC 2 receptor?

upregulation of CD4

what occurs during negative selection of T cells?

T cells are tested against self-antigenswh

what happens if a TCR binds to MHC and a self-antigen?

undergo apoptosis

what are the T cells called if they pass positive selection and negative selection?

self-tolerant

what is the gene that is critical for T cell education and self-tolerance?

autoimmune regulator gene (AIRE)

where is the AIRE gene expressed?

thymic medullary epithelial cells with MHC molecules

what happens if this gene is lacking?

autoimmune diseases

how does a bursectomy affect the ability to produce antibodies?

total circulating lymphocytes decreased, humoral immunity (antibody concentration) markedly decreased

how does a thymectomy affect the ability to produce antibodies?

No T cells in secondary lymphoid tissue or circulation, cause defective T cell mediated immunity

how do defects in gene rearrangement alter the ability to produce antibodies?

severe combine immunodeficiency, cannot develop B or T cells

what are the functions of the secondary lymphoid tissue?

antigen trapping, clonal expansion, develop immunological memory

how is immunological memory beneficial to the host?

long term immunity; more potent immune response upon re-encounter with the same antigen; lasts a lifetime; generated in secondary lymphoid organs

when is the immunological memory formed?

during the primary immune response

what is an effector lymphocyte?

lymphocytes that have come in contact with an antigen and are “activated”

where are T cells located in the lymph nodes generally?

paracortex

where are B cells found within a lymph node?

follicles

where are T cells found within the spleen?

PALS - periarteriolar sheath

where are B cells found in the spleen?

white pulp, follicles

what is the process of chemotaxis?

movement of the cell in a response to a chemical stimulus

what is a chemokine?

cytokines that direct chemotaxis; tells cells WHERE to go

what are integrins?

transmembrane cell adhesion proteins and signaling receptors

What is the HEV?

high endothelial venules

what is the function of HEV?

specialized blood vessels that mediate lymphocyte trafficking to lymph nodes; “sticky” for naive lymph nodes

which chemokine receptors are on dendritic cells that home the cell to the paracortex?

• CXCR4

• CCR7

what ligand does CXCR4 on DC bind to on the paracortex?

CXCL12

what ligand does CCR7 on DC, T cell, and B cell bind to on the paracortex?

CCL19 and CCL21

which specific molecules interact to attract the T cell and B cell to the HEV?

CD62L on the T/B cell interacts with CD34/GlyCAM-1 on HEV

What occurs to the CCR7 and CD62L when the T cell is activated?

CCR7 and CD62L are shed to allow the T cell to leave the paracortex and go towards inflammation sites

what receptor and ligand homes B cells to LN follicles?

CXCR5 on B cells bind to CXCL13 in follicles

what are the 3 signals for T cell activation

1. antigen-specific

2. co-stimulation

3. Cytokines

what is the function of signal 1 (antigen specific) in T cell activation?

engagement of the TCR to MHC:peptide complex (antigen)

What are the specific receptors and ligands involved in signal 1 in T cell activation?

TCR, CD3, CD4, CD8

what are TCR?

t cell receptor

what does CD3 assist in?

assists in signal transduction

what is the purpose of CD4 on T cells?

specify MHC class 2; bind to MHC class 2 on APC and involves extracellular antigens

what is the purpose of CD8 on T cells?

specify MHC Class 1; interact with MHC 1 on all nucleated cells and involves intracellular antigens

What is the purpose of signal 2 (co-stimulation) in T cell activation?

acts as a 2 factor authentication

what are the ligands that are involved with co-stimulation during T cell activation?

• CD154 on T cell binds to CD40 on APC

• CD28 on T cell binds to B7 on APC

what effect does the binding of CD154 on T cells to CD40 on APC during co-stimulation cause?

DC releases cytokines; upregulates CD28 on T cell

what effect does the binding of CD28 on T cells binding to B7(CD80/CD86) on APC cause?

enhances cytokine expression and survival genes in T cell; upregulates CTLA-4 expression

what does the binding of CTLA-4 to CD80/CD86 2-3 days later cause?

STOPs activation

what is the purpose of the signal 3 in T cell activation?

Stimulate proliferation of T cells

what cytokines are involved in the proliferation of T cells during activation?

IL-2

how is T cell activation regulated?

peripheral tolerance outside of primary lymphoid tissue to prevent autoimmunity

what occurs if APC only has specific peptide:MHC complex and no co-stimulatory molecule?

the T cell becomes anergic

what occurs if the T cell only binds to the co-stimulatory molecule?

nothing will occur

what type of cell do naive B cells have to encounter to receive survival signals to continue circulation in order to find their antigen?

follicular dendritic cell

what happens to the B cell if it binds to its antigen?

waits in T cell zone until a matching T cell binds to form a pair

how are pig lymph nodes different from dogs?

• considered “inside out” - cortex on the inside and medulla on the outside

• do not contain lymphocytes in lymph

• circulation = bloodstream → HEV → lymph node paracortex → efferent vein

what is the circulation through the dog lymph node?

bloodstream → HEV → lymph node paracortex → efferent lymphatics → thoracic duct

what special secondary lymphoid structures do ruminants and cervids have?

hemal nodes; contian B cells in cortex and T cells at the center

what are the two functions of splenic red pulp?

• removes aged blood cells and immune complex coated cells

• salvage iron and bilirubin from red cells

what structures does white pulp contain?

contain marginal zone, follicles, PALS; does NOT contain HEV

what are MALT tissues?

tonsils, GI (GALT), bronchial (BALT), Nasal (NALT), urogenital

how can bone marrow act as a secondary lymphoid organ?

memory cells and plasma cells colonize; second does of antigen causes bone marrow to release large quantities of antibodies in studies

compare and contrast primary and secondary lymphoid organs:

• source of immune cells

• interaction with foreign material/antigen

• interaction with self antigen

• negative or positive selection

what are the T cell subtypes?

Th1, Th2, Th17, Tfh, Treg

what are polarizing cytokines?

cytokines that direct the cytokines to differentiate into their subtypes

what are effector cytokines?

cytokines that are secreted by effector cells to perform a function

what is the t cell preceptor for Th1, Th2, Th17, Tfh, Treg?

CD4+ T cells

what cytokines polarize T cells into Th1 cells

IL-12, IFN-gamma