L3- Cellular Immune Response

Question 1

Innate immunity is composed of…

Answer 1

A nonspecific immune response that includes physical barriers, neutrophils, macrophages, monocytes, dendritic cells, natural killer cells, and complement. Unlike the adaptive immune system, it does not provide permanent immunity against pathogens.

Question 2

what is adaptive immunity?

Answer 2

A part of the immune system mediated by antigen-specific cells. Adaptive immunity generally takes effect several days after initial pathogen recognition by the innate immune system. Unlike the innate immune system, the adaptive immune system mounts a more specific and effective immune response and can form memory in order to respond more quickly to reinfection by a previously encountered pathogen.

Question 3

what cells mediate adaptive immunity?

Answer 3

• Antibody - neutralization

* Cytotoxic T cells

Question 4

what are the lymphocytes markers?

Answer 4

• CD3 – all T cells
• CD4 – helper T cells
• CD8 – cytotoxic T cells
• CD19 – B cells
• CD16 & CD56 – NK cells

Question 5

what are the specific CDs of NK cells?

Answer 5

CD16 & CD56

Question 6

T cells originate in the thymus. True/False

Answer 6

False

T cells originate from lymphoid progenitor cells in the bone marrow and mature in the thymus

Question 7

what is the positive selection of T cells?

Answer 7

• -Thymic cortical cells express MHC class I and MHC class II antigens.
• -Tests if T-cell receptors can bind MHC appropriately (not too strongly or too weakly)
• -T cells (CD4+ / CD8+): doubler positives receive survival signal.
• -Dysfunctional T cells then undergo apoptosis.

Question 8

what is the negative selection of T cells?

Answer 8

• -Negative selection of T cells ensures that the thymus does not produce self-reacting T cells
• -Tests if T cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cells
• -T cells that do not bind receive survival signal.
• -Dysfunctional T cells undergo apoptosis.
• -Mediated by the autoimmune regulator protein (AIRE)

Question 9

what is the PCR (T cell receptor?)

Answer 9

• -A receptor present on T cells that recognize and bind antigen-MHC complexes. Also important in the positive and negative selection process of T cell differentiation.
• -Binding of a T-cell receptor to its specific antigen triggers activation of the T cell.
• -This antigen fragment has to bind to the major histocompatibility complex molecule on the surface of another cell in order to be recognized by the TCR.
• -The adaptive immune response is initiated in secondary lymphoid organs, where antigens are presented on the surface of antigen-presenting cells (i.e., macrophages, dendritic cells, B cells).

Question 10

what is the structure of TCR?

Answer 10

The TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (α) and beta (β) chains expressed as part of a complex with the invariant CD3 chain molecules.

Question 11

what is the TCR gene reaarangement?

Answer 11

• -Variable region made up of V, D and J segments
• -100’s different V, D,J gene segments
• -Randomly combine one of the V with a D and/or J
• -Responsible for a diverse repertoire
• -Rearranged at the DNA level – once changed can’t be altered – T cell has receptors with single specificity throughout life

Question 12

what are the RAGs?

Answer 12

A set of genes that encode RAG proteins 1 and 2, which together form V(D)J recombinase, an enzyme required for V(D)J recombination in T cells and B cells. Autosomal recessive RAG1 and RAG2 loss-of-function mutations are a rare cause of severe combined immunodeficiency.

Question 13

can T cell change receptor specificity during life?

Answer 13

no
Rearranged at the DNA level – once changed can’t be altered – T cell has receptors with single specificity throughout life

Question 14

what is the goal of TCR gene rearrangement?

Answer 14

Responsible for a diverse repertoire

Question 15

positive vs negative selection?

Answer 15

• Can interact with self-MHC
POSITIVELY SELECTED
Don’t waste energy making cells that cannot protect you
• Don’t interact strongly with self-peptide
NEGATIVELY SELECTED
–Prevents autoimmunity

Question 16

what are the secondary lymphoid organs?

Answer 16

Specialised organs which enhance the chance oflymphocytes meeting cognate antigen.
• Lymph nodes
• Spleen
• MALT
A lymphoid organ in which immune cells interact with extrinsic antigens to generate an antigen-specific response. Secondary lymphoid organs include the spleen for blood-borne antigens, the lymph nodes for antigens in lymphatic fluid, tonsils for inhaled antigens, and the Peyer patches for ingested antigens.

Question 17

what are the 2 pathways of antigen presentation?

Answer 17

• All nucleated cells
Endogenous Pathway
• Antigen presenting cells
Exogenous Pathway
–Exogenous antigens are presented via MHC II to TCR/CD4.
–Endogenous antigens, cross-presentation of antigens are presented via MHC I to TCR/CD8.

Question 18

MHC vs HLA?

Answer 18

The terms MHC and HLA are often used interchangeably, although they are not the same. While MHC refers to cell membrane proteins, HLA refers to the gene complex that encodes the receptors and numerous other defense proteins. MHC are also a product of this gene complex.

Question 19

structure of MHC 1?

Answer 19

Comprised of two polypeptide chains of different length: The long chain contains the alpha domains (α1, α2, α3), the short chain is the peptide β2-microglobulin and carries the β2 domain.

Question 20

what is the role of MHC 1?

Answer 20

Continuously presents endogenous fragments of proteins located in the cell, which allows for rapid detection and destruction of cells in infections with intracellular pathogens (e.g., viruses) and cells that produce atypical proteins (neoplastic or malignant cells) → cytotoxic T‑cell reaction

Question 21

MHC 2 is composed of…

Answer 21

Comprised of two polypeptide chains of equal length (alpha and beta) that each contain two domains (α1, α2 and β1, β2)

Question 22

what is the role of MHC 2?

Answer 22

• -Antigen-presenting cells can ingest exogenous material (extracellular pathogens) into fragments via phagocytosis and present them on the cell surface via MHC class II receptors.
• -MHC II-antigen complexes are assembled in acidified endosomes after the release of the invariant chain.
• -Antigen presentation leads to the activation of CD4+ T lymphocytes, which then activate B lymphocytes and, thus, provides a connection between innate and adaptive immunity.

Question 23

what is the invariant chain?

Answer 23

A polypeptide involved in the formation of the peptide-binding groove of MHC class II molecules. Also involved in subsequent export of MHC class II molecules from the endoplasmic reticulum.

Question 24

MHC 1 vs 2 antigen processing?

Answer 24

1)Antigens are peptides, lipids, or polysaccharides which are transported to the RER via transporter associated with antigen processing (TAP).
–MHC I-antigen complexes are assembled in the RER.
–The polymorphic zone presents antigens derived from within the cell. The nonpolymorphic zone binds to CD8 T lymphocytes.
2)Antigen-presenting cells can ingest exogenous material (extracellular pathogens) into fragments via phagocytosis and present them on the cell surface via MHC class II receptors.
MHC II-antigen complexes are assembled in acidified endosomes after the release of the invariant chain.

Question 25

do MHC 1 uses acidified lysosomes to process antigens?

Answer 25

no | MHC 2 uses that

Question 26

Does T cell activation occur in primary or secondary lymphoid organs?

Answer 26

- - T cell activation (differentiation into effector T cells following antigen presentation.) mainly occurs in secondary lymphoid organs, such as lymph nodes. - -Dendritic cells travel through different tissues, phagocytize fragments of pathogens or malignant/virus-infected cells, process the antigens, and then migrate through afferent lymphatic vessels to a lymph node to present these antigens via MHC I and II

Question 27

what are the signals that are required to activate T cells?

Answer 27

- -Signal 1: TCR-Peptide-MHC - -Signal 2: Co-stimulatory Molecules - -Signal 3 or Danger Signal: cytokines stabilized by adhesion molecules

Question 28

what are the co-stimulatory signals required to activate T cells?

Answer 28

1) Co-stimulatory signal: Interaction of the second set of molecules mediates the survival and proliferation of T cells. - -On the dendritic cell: B7 protein (CD80 or CD86) - -On the T cell: CD28 2) An antigen presentation without this co-stimulatory signal will lead to T-cell anergy.

Question 29

what is the signal 1 one for T cell activation?

Answer 29

• TCR recognizes specific peptide on MHC molecule • CD4/CD8 co receptor interacts with residues on the side of MHC • Activation of signalling molecules associated with TCR complex • Activate gene expression program • T cell is primed but requires signal 2 to become fully activated --Exogenous antigens are presented via MHC II to TCR/CD4. --Endogenous antigens, cross-presentation of antigens are presented via MHC I to TCR/CD8.

Question 30

what is signal 2 for T cell activation?

Answer 30

* Costimulatory receptors (B7 or CD80/CD86) on APCs are upregulated * Binds to a costimulatory receptor on T cell (CD28) * CD28 always present – once it engages CD80/86 then T cells properly activated

Question 31

does CD 28 need to be upregulated for T cell activation?

Answer 31

no | CD28 always present – once it engages CD80/86 then T cells properly activated

Question 32

describe cellular‑mediated response via Th1 cell (CD4+)

Answer 32

1) Activated via antigen presentation by MHC class II receptors 2) Immune response to intracellular pathogens (viruses, intracellular bacteria) - -Release cytokines (including IFN‑γ, IL‑2, and TNF‑α) → cytokines stimulate macrophages (positive feedback) and CD8+ cytotoxic T cells: these cytokines inhibit the type 2 response (negative feedback) and activate the type 1 response (positive feedback). - -IFN‑γ, IL-2, and TNF‑α induce granuloma formation against foreign bodies that cannot be eliminated by the immune cells. - -role in autoimmune diseases

Question 33

describe cellular‑mediated response via Th2 cell (CD4+)

Answer 33

1) Activated via antigen presentation by MHC class II receptors 2) Immune response to extracellular pathogens (bacteria, parasites) - -Release cytokines (including IL-4, IL-5, IL-13) which stimulate eosinophils, basophils and mast cells - role in allergic diseases

Question 34

what cytokines are involved in TH2 response?

Answer 34

IL-4, IL-5, IL-13

Question 35

what is the role of cytokines produced in TH2 response?

Answer 35

1) IL-13: A cytokine that is primarily produced by Th2 CD4 cells. It activates the alternative macrophage activation pathway and acts on B cells to induce isotype switching to IgE 2) IL-4: A cytokine produced by Th2 cells that promotes differentiation of naive CD4+ T cells to produce additional Th2 cells (positive feedback). Also induces class switching of B-cells from IgM-producing to IgG- and IgE-producing subtypes. 3) IL-5: A cytokine secreted by mast cells that stimulates eosinophil proliferation and activation. Also secreted by T cells to promote B cell differentiation and class switching to IgA.

Question 36

what is the role of IL-17?

Answer 36

A pro-inflammatory cytokine produced by T helper 17 (Th17) cells in response to interleukin-23 signaling. Involved in chemokine induction that attracts monocytes, macrophages, and neutrophils to the site of inflammation. Associated with some autoimmune diseases. Deficiency of IL-17 causes chronic mucocutaneous candidiasis.

Question 37

TH-17 deficiency leads to...

Answer 37

Hyper-IgE syndrome A condition caused by a mutation in STAT3 that results in Th17 cell deficiency and, thus, impaired neutrophil recruitment to sites of infection. Characterized by increased serum IgE concentrations. Manifestations include coarse facial features, recurrent abscesses, retained primary teeth, and eczema.

Question 38

what are the superantigens?

Answer 38

• Bind outside of HLA loop and relatively well-conserved part of TCR • Activate large portions of the T cell repertoire • Massive cytokine surge – sepsis syndrome • Overwhelm regulatory T cells Unlike normal antigens, superantigens do not have to be processed and presented by macrophages for recognition by specific T cells. Superantigens bind directly to the MHC II complexes of T cells, resulting in widespread polyclonal T-cell activation. Exotoxins produced by certain bacteria are important examples of superantigens (e.g., TSST-1 toxin produced by S. aureus can result in toxic shock syndrome).

Question 39

what are the CD4 T cell subtypes?

Answer 39

``` • Defined by cytokine production profile • Helper T cells – Th1 – Th2 – Th17 • Regulatory T cells ```

Question 40

what are the regulatory T cells?

Answer 40

A type of T cell that limits and downregulates the immune response, including the prevention of autoimmune disease by maintaining tolerance to self-antigens. Expresses CD4 surface marker.

Question 41

which T cell response results in granuloma formation? TH1 or TH2?

Answer 41

TH1 - -Antigen-presenting cells present antigens to CD4+ Th cells and secrete IL-12 → stimulate differentiation into Th1 cells → Th1 cells activate macrophages by secreting IFN-γ → macrophages release cytokines (e.g., TNF), which stimulates the formation of epithelioid macrophages and giant cells - -Epithelioid cells secrete TNF-α, which serves to maintain the granuloma.

Question 42

how T cell function is assessed?

Answer 42

* Clinical History – infections/vaccine problems * HIV * Lymphocyte counts * T cell numbers & subtypes * Expression of TCRs, cytokine receptors etc * Delayed hypersensitivity skin tests * Vaccination with protein antigens * Proliferation assays