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H&D > Wk 1 Antigen Presentation & Lymphocyte Development > Flashcards

Wk 1 Antigen Presentation & Lymphocyte Development Flashcards

1
Q

What can B cell receptors bind?

A

Soluble, free-floating antigens

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2
Q

What do T cell receptors bind?

A

Only small peptide antigens (8-20 aa) presented by MHC on the cell surface of APCs

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3
Q

What are the two classes of MHC?

A
  1. Class I on APC binds CD8+ T cells
  2. Class II on APC binds CD4+ T cells
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4
Q

What are the 3 MHC Class I genes?

A

HLA-A,
HLA-B,
HLA-C

HLA = human leukocyte antigen
HLA = MHC

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5
Q

What are the 3 MHC Class II genes?

A

HLA-DP
HLA-DQ
HLA-DR

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6
Q

What is MHC inheritance?

A

Inherited w/ co-dominant expression - 2 alleles of each
-all nucleated cells express MHC Class I
-professional APCs (dendritic cells, macrophages, B cells) also express MHC Class II
-Histocompatibility genes are inherited as a group (haplotype), one from each parent. Thus, HLA genes are co-dominantly expressed in each individual. A heterozygous human inherits one paternal and one maternal haplotype, each containing three class I (A, B, and C) and three class II (DP, DQ, and DR) loci

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7
Q

What is the difference b/w MHC Class I and II molecular structures?

A

MHC Class I: Single a chain forms peptide binding cleft, surface expression stabilized by a small molecule called b2-microglobulin.

MHC Class II: a and b chains that come together to form peptide binding cleft.

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8
Q

What are the T cell co-receptors for CD4 and CD8?

A

CD4 -> MHC Class II
CD8 -> MHC Class I

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9
Q

What are MHC most of in the human genome?

A

The most polymorphic
-each can bind a different set of peptides
-gives us as many opportunities as possible to bind variety of pathogens

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10
Q

How do MHC molecules behave under non-infectious conditions?

A

MHC molecules are not stable unless bound to something, so bind to self peptides

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11
Q

What do MHC do under infectious conditions?

A

MHC presents foreign peptides derived from pathogens to T cells

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12
Q

TCR always need to recognize self and foreign antigen when binding to MHC

A
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13
Q

What are MHC Class I peptides derived from?

A

cytosolic antigens (think viruses)

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14
Q

What do MHC Class II present?

A

Peptides from extracellular antigens that have been phagocytosed

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15
Q
A
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16
Q

Where are MHC Class I formed?

A

in ER

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17
Q

How do many viruses evade T cell responses?

A

By interfering w/ antigen presentation on MHC Class I
-turn off fxns

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18
Q

MHC Class II antigen processing

A

-assembled in ER by complexing w/ invariant chain (Li) and blocking the binding of peptides

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19
Q

MHC Class II Ag processing summary

A
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20
Q

What is cross-presentation?

A

Process whereby antigens derived from phagolysosomes can be exported into cytosol and can enter into MHC Class II molecule presentations
-a specialized fxn of dendritic cells

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21
Q

Important

A

Dendritic cells are required for activation of naïve T cells.
* Activated CD8+ T cells can target infected nucleated cells, as they all express MHC I.
* Activated CD4+ T cells interact with MHC II-expressing macrophages and B cells to enhance their function.

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22
Q

What’s the difference b/w B cell receptors and antibodies?

A

BCR is attached to membrane
Antibodies are free floating

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23
Q

Explain the structure of the antibody

A

–2 identical heavy chains
–2 identical light chains
=> bivalent
–immunoglobulin domains
–Variable region mediates antigen recognition
–Hinge region allows flexible multi- valent binding
–Constant (Fc) region mediates effector functions:
*Complement activation
*Opsonization
*Cellular activation (Fc receptors)

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24
Q

What are the 3 roles of the Constant (Fc) region?

A
  1. complement activation
  2. opsonization
  3. cellular activation (Fc receptors)
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25
Q

How many antigen receptor types does each naive or resting B cell express?

A

1 cell = 1 specificity
-1 antigen receptor type that’s either membrane-bound or secreted
-activated B cells can differentiate into antibody-producing plasma cells

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26
Q

How many antigen receptors does each naive or resting B cell express?

A

1 cell = 1 specificity
-1 antigen receptor type that’s either membrane-bound or secreted
-activated B cells can differentiate into antibody-producing plasma cells

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27
Q

What switches on B cells to change antibody isotypes?

A

Constant region

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28
Q

5 antibody types

A
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29
Q

What antibody type is found in the gut?

A

IgA

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30
Q

What antibody is the most abundant?

A

IgG

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31
Q

What B cell region binds to antigens?

A

The variable region (which is composed of hypervariable aa sequences that determine specificity) and is made of the heavy and light chains

32
Q

Where are TCRs?

A

Only membrane bound

32
Q

What is the structure of TCR like?

A
  • TCR: a/b (conventional) or g/d
  • Structurally related to Ig.
  • Does not recognize free antigen.
  • Peptide antigens presented by the
    major histocompatibility complex
    (MHC) molecules.
  • No Fc region: effector function
    mediated by the T cell, not the TCR
    -will either secrete cytokines or kill target
33
Q

What is the defining marker of T cells?

A

CD3

34
Q

Where does lymphocyte activation occur?

A

In secondary lymphoid organs, incl spleen and lymph nodes

35
Q

4 steps in lymphocyte development

A
  1. cytokine-driven lymphoid development: survival and expansion
    • selection: successful antigen receptor rearrangement
  3. (-) selection: elemination of reactivity to self-antigens
  4. Egress to secondary lymphoid tissues
36
Q

What is the role of IL-7?

A

Lymphoid lineage commitment (lymphopoiesis)
-impaired IL-7 -> signaling defective T and B cell development -> SCID

37
Q

How are diverse antigen receptors generated?

A

DNA recombination

38
Q

How does DNA recombination create diverse antigen receptors?

A
  1. Recombination-activating gene (RAG) recombinase - cuts and pastes regions - randomly recombines VDJ
  2. TdT = terminal deoxynucleotide transferase - randomly inserts nucleotides into sites of recombination to enhance diversity - messy process, most don’t give rise to coding region
  3. RNA splicing determines constant regions - either mu or delta (IgM or IgD)
39
Q

What happens during positive selection?

A
  1. combination of germline gene segments (VDJ) by RAG recombinase
  2. Addition of extra nucleotides by TdT at recombination sites
  3. combination of 2 chains
  4. each B and T cell has its own unique antigen receptor
40
Q

BCR vs TCR

A
41
Q

4 steps of B cell positive selection

A
  1. productive rearrangment results in intracellular signal to cell (+ signal). W/o signal, cell -> apoptosis
  2. 2 chances for productive heavy chain rearrangement (1 locus, 2 alleles)
  3. 4 chances for productive light chain rearrangement (2 loci, 2 alleles each)
  4. Once functioning antigen receptor is expressed, no more rearranging
42
Q

What is X-linked agammaglobulinemia?

A

A defect in positive selection
-Bruton’s Tyrosine Kinase (Btk) (IMP kinase in + selection process)

  1. X-chromosome encodes Bruton’s tyrosine kinase (Btk) found in pre-B cells.
  2. Btk signals cell that a productive antigen receptor is present at the cell surface.
  3. Btk deficiency leads to lack of Bcells: X-linked agammaglobulinemia.
  4. Autosomal recessive versions as well.
43
Q

Explain B cell negative selection

A
44
Q

What is a thymocyte?

A

committed T cell progenitors that have migrated from the bone marrow to the thymus
-majority of cells in thymus

45
Q

What is a thymocyte?

A

committed T cell progenitors that have migrated from the bone marrow to the thymus
-majority of cells in thymus

46
Q

What occurs in thymus?

A

Site of T cell (+) and (-) selection
-thymic epithelial cells assist selection

-genetic loss = DiGeorge syndrome can -> severe immunodeficiency

47
Q

What are the 3 processes in thymus?

A
  1. Positive selection part I: Productive TCR rearrangement and expression (cortex)
  2. Positive selection part II: recognition of host MHC by new TCRs (cortex)
  3. Negative selection: removal of auto-reactive thymocytes (medulla)
48
Q

What is positive selection of T cells?

A

Recognition of self MHC in thymic cortex

49
Q

What and where are double positive thymocytes?

A

In thymus
CD4+ and CD8+

50
Q

Explain negative selection of T cells

A

In medulla
= removal of auto-reactive T cells

51
Q

Di George Syndrome

A

=a defect in thymic development -> partial or complete lack of thymic development
* Other defects: structural defects in face and pharynx, hypoparathyroidism, cardiovascular, neurological.
* “Complete”DiGeorge=nothymic development, severe lack of T cells. Only 1% of cases. Susceptible to opportunistic infections, death in the first couple of years. Treatment is thymic transplant.

52
Q

What is L-selectin?

A

Preferentially attracts naive lymphocytes
-located in high endothelial venule (HEV) in lymph node
-Naïve T and B cells express high levels of L-selectin and traffic to secondary lymphoid organs via High Endothelial Venules.

53
Q

Trafficking to T cell and B cell zones

A

IL-7 drive lymphoid commitment and survival signals
BAFF = B cell activating factor

54
Q

What is TACI?

A

TACI inhibits B cell expansion and promotes the differentiation and survival of plasma cells
=Transmembrane activator calcium modulator
-~10% deficiency in CVID (common variable immunodeficiency)

55
Q

Key points

A
55
Q

Key points

A
56
Q

What types of molecules can B cells respond to?

A

Many - lipids, sugars, nucleic acids, etc
-protein antigens induce best Ab responses since they can mobilize Th cells too

57
Q

What does direct antigen-mediated activation of B cells induce?

A

Short-lived IgM responses from short-lived plasma cells w/ limited clonal expansion

58
Q

What can provide costimulatory signals to B cells?

A

Toll-like receptor ligands (ie LPS) and complement fragments

59
Q

What happens to antigens before they’re expressed to T follicular helper cells (Tfh)?

A

They’re phagocytosed, then expressed on the APC w/ CD40

60
Q

What happens to antigens before they’re expressed to T follicular helper cells (Tfh)?

A

They’re phagocytosed, then expressed on the APC (B cell) MHC Class II molecules w/ CD40

61
Q

What are 2 things the Tfh cells do to help mediate the activation of B cells?

A
  1. Express CD40L, which binds to CD40 on surface of B cells as costim pathway
  2. secrete cytokines (differ based on Tfh response) - can include IL-4, IFNgamma, IL-21 —–cytokines drive isotype switching
62
Q

5 steps of T cell help to B cell clonal expansion

A
  1. B cells internalize antigens that bind B cell receptors
  2. Antigens are degraded in endosomes and presented on MHC Class II
  3. Tfh effector cells specific for the same antigen bind to MHC Class II
  4. T cells induce B cell activation via the CD40 on B cells /CD40L on T cells costimulatory pathway
  5. T cells induce B cell activation through cytokine production -> B cell clonal expansion and formation of the Germinal Center
63
Q

What is AID?

A

=activation-induced deaminase
-activated by CD40
-goes to nucleus and mediates:
1. isotype class switching of Ig constant region
2. somatic hypermutation of the VDJ region

64
Q

What are the 2 critical processes that AID initiates in the germinal center?

A
  1. isotype class switching of the Ig constant region by initiating DNA recombination
  2. somatic hypermutation of the VDJ region
65
Q

How does isotype class switching happen?

A

AID initiates DNA recombination to switch from one constant region to another
-selection of constant regions is driven by cytokines
-one way event: upstream constant regions are excised from the genome
-IgM -> IgG next, IgA, IgE

66
Q

What is somatic hypermutation?

A

DNA mutagenesis within the VDJ region of the immunoglobulin genes
-mediated by AID
-most mutations disrupt antigen binding affinity and -> apoptosis
-some mutations may increase affinity -> proliferation

67
Q

What is affinity maturation?

A

Multiple rounds of somatic hypermutation and subsequent selection of higher affinity variants -> the emergence of high affinity B cell clones

68
Q

What role do follicular dendritic cells play in affinity maturation?

A

They promote affinity maturation by retaining antigens in the germinal center for weeks or months after pathogen clearance
-prolongs process of affinity maturation
-very high affinity IgG can take months to fully mature

69
Q

What is the result of somatic hypermutation and affinity maturation?

A

Formation of long-lived plasma cells and memory B cells

70
Q

What isotype/class are memory B cells?

A

Mostly IgG, IgA, IgE

71
Q

What are 3 characteristics of long-lived plasma cells?

A
  1. persist for years
  2. reside in BM
  3. continuous antibody secretion
72
Q

Compare a single exposure w/ no T cell help, single exposure w/ T cell help and second exposure to antigens

A
73
Q

T cell and B cell formation summary

A
74
Q

4 antibody effector mechanisms

A
  1. Neutralization (all isotypes) - prevent infection, prevent colonization and block bacterial toxins
  2. opsonization (IgG - b/c many phagocytes express receptors called Fc gamma receptors for the constant region of IgG antibodies coating the pathogens
  3. complement activation by IgG and IgM, which -> MAC formation -> lysis of target bacteria AND/OR complement opsonizes the pathogen for enhanced phagocytosis
    -complement fragments (eg C5a) -> vasodilation and inflammation
  4. Mast cell activation by IgE upon 2nd exposure -> degranulation -> histamines and leukotriene release -> allergic response
  5. ADCC (antibody-dependent cell-mediated cytotoxicity) mediated by IgG - occurs when NK cells express Fc gamma receptors that bind to constant region of IgG molecules & can then recognize the viral GPs on infected cells and release Granzyme B and Perforin
75
Q

Summary

A

H&D (23 decks)

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