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Immunology > Assignment 8 > Flashcards

Assignment 8 Flashcards

1
Q

when progenitor T cells migrate to the thymic cortex for development/differentiation/maturation, what the this event marked by?

A

sequential expression of cell surface proteins (receptor/ligands)

-expression of TCR that is defined by its exquisite specificity in recognizing antigenic peptide displayed as a complex with MHC molecules

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2
Q

what influences the naive mature B cells to differentiate in the thymic microenvironment?

A

IL-7

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3
Q

during its migration through the thymus, the thymocyte expresses unique TCR capable of recognizing antigenic fragments ONLY when?

A

the peptide fragments are displayed in association with either a class I or II MHC molecule

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4
Q

what results in the acquisition of a unique TCR to an array of T cells each expressing a different TCR?

A

somatic recombination

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5
Q

what are TCR composed of (types of TCR..)?

A

2 transmembrane polypeptide chains - either alpha/beta (90% of T cells in human body) or gamma/delta

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6
Q

what is the TCR expressed in association with?

A

5 invariant polypeptides collectively termed CD3

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7
Q

what is the role of CD3

A

link the antigen binding receptor to the T cell with signaling pathways

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8
Q

what regions are found on each chain of the T cell receptor?

A

variable and constant regions

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9
Q

T cell clones express TCR with the _____ constant regions, each T cell clones express TCR with a ____ variable region

A

same
unique

*why - variable regions - VDJ
TCRalpha variable region = VJ
TCRbeta variable region = VDJ

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10
Q

what is the T cell repertoire a result of

A
  • multiple copies of germ line VDJ gene segments
  • random selection and combo of VDJ gene segments
  • junctional diversity generated by the addition/deletion of bases
  • random assortment of TCRalpha and TCRbeta chains
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11
Q

during T cell differentiation in the thymic cortex, what molecules are expressed on the cells surface

A 
CD2
Pre-TCR-CD3 complex
CD4
CD8
TCR-CD3 complex
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12
Q

what is the first molecule to be expressed and what it is considered

A

CD2
expressed throughout cell life
“pan marker”

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13
Q

why does CD3 continue to be expressed throughout cell life?

A

because TCRs are only expressed on cell surface complexed WITH CD4

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14
Q

although pre-TCR is only transiently expressed, what critical role does it play?

A

that the pre-TCR complex can only form on the developing thymocyte if the TCR beta chain variable region has been successfully recombined in the process of somatic recombination

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15
Q

expression of pre-TCR CD3 indentified developing thymocytes that have potential to express what?

A

viable TCR

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16
Q

what role does signaling via the CD3 molecules of the pre-TCR complex play in subsequent differentiation of the thymocyte

A
  • proliferation of that developing thymocyte
  • expression of CD4 and CD8 (Double positive thymocyte) –then become CD4+ or CD8+, but not both! (single positive)
  • delivery of signal that direct somatic recombination of the TCR alpha chain
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17
Q

define somatic recombination in terns of TCR variability

A

process by which unique variable regions are created in the thymus

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18
Q

what initiates the recombination process of TCR?

A

recombinases, nucleoprotin products of the RAG-1 and RAG-2 genes

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19
Q

what happens during differentiation of T cell

A

the DNA in the locus that encodes variable regions is cut and recombined to make an intact gene for the variable region in the alpha chain and beta chain = rearranged gene can be transcribed to mRNA the translated into an alpha chain and bet polypeptide chain

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20
Q

how many identical TCRs are be on any given cells

A

25,000 - identical!

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21
Q

clones that express TCR receptors represent what

A

t cell repertoire

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22
Q

somatic recombination of the TCR ___ variable region occurs before TCR____

A

beta

alpha

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23
Q

how is TCR diversity made possible?

A

because of somatic recombination of the VDJ segments that encode the variable regions

  • multiple germline genes
  • combinational association
  • junctional diversity - from Tdt
  • random selection of alpha/beta chains
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24
Q

what is the role of recombinase activating genes (RAG-1 and RAG-2)

A

recombination process requires these to be acitvated

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25
Q

what is the role of terminal deoxynucleotidyl transferase

A

incorporation of nucleotides at junctions is mediated by template independent DNA polymerase called Tdt

26
Q

explain allelic exclusion. What does it prevent?

A

-Inhibition of somatic recombination on the other allele
-Prevents two different α chains being expressed with a β chain which would result in two different
antigenic specificities—> bad

27
Q

define T cell repertoire. What do the clines expressing TCR represent?

A
  • There can be as many as 25,000 identical TCRs on any given cell
  • Clones expressing these receptors represent the t-cell repertoire
28
Q

Describe the steps of T-cell developmental pathway from stem cell (bone marrow) to mature CD4+, CD8+ T cell (thymus)

A
  • Self renewing stem cell
  • Pluripotent stem cell
  • Lymphoid progenitor
  • T-cell progenitor
  • Thymus migration
  • Growth only occurs in the thymus with presence of cytokine IL-7
29
Q

define positive selection (cortex)

A
  • When the t-cell receptor recognizes an MHC

- Proliferation occurs – appropriate interactive avidity

30
Q

Define Negative selection for double positive (cortex/medulla)

A
  • the t-cell receptor recognizes an MHC but the avidity is too high
  • apoptosis – very high interactive avidity
31
Q

explain death by neglect (cortex)

A
  • When the t-cell receptor does not recognize an MHC

- Death – negligible interactive ability

32
Q

what is the final phase a T cell has to go through?

A

negative selection for single positive thymocytes (medulla)

33
Q

what occurs during negative selection for single positive thymocytes?

A

high interactive avidity with bone marrow derived APC

CD4 pr CD8 interaction with MHC occurs

34
Q

explain lineage selection

A

-refers to the transition of a double positive thymocyte (CD4+,CD8+) to a single positive thymocyte expressing either CD4 or CD8 but not both
-silencing of either the CD4 or CD8 gene occurs in each individual T cell
-t-cell lineages are classified by the expression of CD4 or CD8 – reflective of subsequent
biological activity (cytokine secretion or killing)

35
Q

define double positive thymocytes. when does it occur?

A

cell surface expression of both CD4 and CD8 on the developing thymocyte – occurs early in phase II

36
Q

define single positive thymocytes

A

-transition of a double positive thymocyte (CD4+,CD8+) to a single positive thymocyte
expressing either CD4 or CD8 but not both

37
Q

explain the term interactive avidity and list four factors on which interactive avidity depends

A
  • Interactive avidity determines fate of double positive T-cell based on
  • # ofTCRonT-cell
  • # of MHC molecules on APC
  • amount of intrinsic affinity of TCR for MHC peptide
  • # adhesion molecules
  • # antagonistic molecules
  • There are approximately 25,000 t-cell receptors on a cell
38
Q

how do naive T cells get into lymph?

A

HEV

glycocalyx of endothelial cells trap T cells

39
Q

describe the t cell movement through the lipid bilayer by extravasation

A

• l-selectin - grabs t-cell
• integrins (LFA-1) – makes t-cell sticky
• matrix metalloproteinases – degrade collagen to make channels in basement
membrane for t-cells
• transendothelial migration of lymph into tissue

40
Q

What happens in the absence of antigen recognition ?

A

lymphocytes exit via efferent lymphatics and enter main lymphatic circulation

41
Q

when T cells express TCR that are autoreactive, how are they killed?

A

die passively in the thymus

42
Q

tolerance induction and screening/selection can only occur after what?

A

thymocyte expresses the TCR-CD3 complex

43
Q

screening occurs on _____ cells

A

double positive - CD8+ and CD4+

44
Q

what does interactive avidity of double positive thymocytes and their TCR with self-antigen/MHC complex depend on?

A
  • intrinsic affinity of the TCR for self antigen/MHC complex
  • density of TCR
  • density of self antigen/MHC complexes on thymic epithelium
  • density of antagonist peptide complexes
45
Q

what occurs during negative selection

A

if recognition exceeds a pre-determined threshold
thymocytes are clonally eliminated or inactivated

consequence of high avidity interactions of TCR for self-antigen/self MHC
occurring in the absence of CD4/CD8 interaction with appropriate MHC

46
Q

where does negative selection take place?

A

thymic cortex

47
Q

where does a more finely tuned process of negative selection occur

A

thymic medulla

note that the process is acting on already positively selected single positive thymocytes

does occur with interaction of CD8 and CD4 with class I and II MHC

48
Q

define death by neglect

A

insignificant avidity with thymic epithelial cells results in death by neglect

49
Q

define positive selection

A

occurs when the avidity of recognition is intermediate (between the 2 extremes of death by neglect and negative selection)

death by neglect — positive sel — neg sel

50
Q

where does the silencing of either the CD4 or the CD8 gene occur

A

in each individual T cell => classifies the T cell as CD4 or CD8!
the function of the T cell is determined at this stage!

51
Q

in negative selection in the cortex, where are the APC dervied?

A

thymic epithelium

52
Q

in negative selection in the medulla, where are the APCs derived?

A

bone marrow

53
Q

the number of self proteins to which the developing T cell is exposed in the thymic medulla is much ____ as a result in the expression of what?

A

greater

AIRE gene

54
Q

what is the role of the AIRE gene?

A

plays critical role in the promiscuous/ectopic expression of tissue-restricted proteins in the thymic epithelial cells (TECs), particualrly medullary TECs

55
Q

describe APECED syndrome (autoimmune polygrandular syndrome type 1)

A

AIRE gene is mutated
mucocutaneous candidiasis
hypoparathyroidism
autoimmune adrenal insufficiency

primary effects endocrine system

56
Q

where do naive T cells undergo antigen-induced differentiation?

A

in secondary lymphoid tissue following intiial encounter with antigenic peptide-MHC — then their roles are defined

57
Q

what does lymphocyte secretion of matrix metalloproteinases do?

A

degrade collagen to generate channels in the subendothelial basement membrane

58
Q

what are nTregs?

A

naturally produced by the normal thymus as a functionally distinct subpopulation of T cells that leave the thymus where they play an active role in est. and maintaining self tolerance - peripheral tolerance

they are regulatory cells, not effector cells

59
Q

what make up the nTregs? What is their role?

A

CD4+(phenotypical)
CD25+ (phenotypical)
FOXP3+ (transcription factor necessary for development and function of nTregs)

players in controlling self reactive T cells

60
Q

what do humans with mutations in FOXP3 develop?

A

multi-organ autoimmune inflammatory disease (IPEX) - immune dysregulation, polyendocrinopahty, enteropathy, X linked syndrome)

= water diarrhea, eczema, type 1 DM

TX with immunosuppresents

61
Q

depletion of nTregs leads to what

A

tumor rejection

Immunology (12 decks)

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