Lecture 10 Thymocyte selection II
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Lecture 10 Thymocyte selection II. Thymocyte positive selection A word about signaling Demonstration in radiation bone marrow chimeras Implications for transplantation The importance of eliminating mature T cells in bone marrow transplantation Thymocyte negative selection

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Lecture 10 Thymocyte selection II

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Lecture 10 thymocyte selection ii

Lecture 10 Thymocyte selection II

  • Thymocyte positive selection

    • A word about signaling

    • Demonstration in radiation bone marrow chimeras

    • Implications for transplantation

  • The importance of eliminating mature T cells in bone marrow transplantation

  • Thymocyte negative selection

    • The limitations of thymic (central) tolerance

    • The role of ectopic antigen expression & AIRE

  • Reminder about the existence of gd T cells


Positive and negative selection

Positive and Negative Selection

The thymus:

Selects the useful

Ignores the useless

Removes the harmful

Positive Selection

Death by neglect

Negative selection


Figure 5 12 part 1 of 2

Figure 5-12 part 1 of 2

CD4

ab

TCR

CD8

CD4 T cell

CD8 T cell


Lecture 10 thymocyte selection ii

Effects of defined mutations on T cell selection

  • MHC class I deficientNo mature CD8 cells

  • MHC class II deficientNo mature CD4 T cells

  • TAP deficientNo mature CD8 T cells

  • CD8 deficientNo killer cells

  • CD4 deficientNo helper cells

  • CD3 deficientNo T cells

  • RAG deficientNo T cells (or B cells)

  • pTa deficientFew ab T cells

  • No thymus (DiGeorge)No T mature cells

  • No thymocytes (ADA-)No T mature cells


Lecture 10 thymocyte selection ii

The signals from cell surface receptors that lead to positive and negative selection are believe to start with protein phosphorylations followed by poorly understood signal integration that finally leads to changes in transcription of genes determining cell fate and differentiation.


Figure 6 16

Figure 6-16


Figure 5 13

Figure 5-13


Lecture 10 thymocyte selection ii

Bone marrow transplantation

and radiation chimerism

  • This technique relies on several differences between white blood cells and other cell types.

    • White blood cells, especially lymphocytes, are very sensitive to radiation-induced or chemotherapy-induced cell death.

    • Most host cells, including the thymic epithelium are radiation resistant.

    • White blood cells can be reconstituted by repopulation from bone marrow stem cells.

  • Treated recipients are depleted of leukocytes then reconstituted (rescued) with bone marrow (usually depleted of recirculating T cells) or hematopoietic stem cells that give rise to all blood cells.


Lecture 10 thymocyte selection ii

Cells of the immune system

Bone marrow/fetal liver

Thymus

Naïve, resting

lymphocytes in lymph nodes, spleen

Adaptive

Innate


Figure 5 10

Figure 5-10


Figure 5 12 part 1 of 21

Figure 5-12 part 1 of 2

CD4

ab

TCR

CD8


Figure 5 131

Figure 5-13

What happens in a radiation chimera?

Positive selection to host cortical epithelial cells

Radioresistant

host type

Bone marrow derived

Donor type

Negative selection to donor and host MHC


Lecture 10 thymocyte selection ii

Host type controls MHC restriction of T cell repertoire

B

AXB

A

AXB


Lecture 10 thymocyte selection ii

Development of Major Histocompatibility

Complex Restriction Patterns in Bone Marrow Plus Thymic Chimeras

See next slide for explanation


Explanation of the chimera experiment

Explanation of the chimera experiment

  • This is the radiation chimera experiment that you will need to understand.

  • The nomenclature is bone marrow donor -> irradiated recipient. Thus an F1 -> parent is an irradiated mouse of strain A reconstituted with bone marrow from strain (AxB)F1. Please understand this.

  • In an F1 -> parent chimera, the F1 T cells mature in the epithelial environment of the parent that expresses only one of the two SETS of alleles. This skews the population to express TCRs that recognize the parental alleles at some moderate affinity.

  • Although I didn’t go into the second line of this experiment, it is accurate, and actually makes a separate point. This would be the parent -> F1. If bone marrow from the A strain is used to reconstitute an irradiated (AxB)F1, then the T cells will be selected to recognize both strain A and strain B. The APCs will express only MHC from strain A (bone marrow origin), and thus the virus will be presented only on strain A. Thus, despite the fact that the T cell population has the potential to respond to either A or B, the antigen is presented only on A, and thus in the virus-response, the only the T cells restricted to virus + A will be expanded.

  • The last two lines show that the MHC allele expressed by the thymus epithelium restricts the population to the recognition of antigen peptides presented by MHC allele of the thymus--despite the fact that, in these mice, the antigen peptides are presented by both a and b alleles.


Figure 5 101

Figure 5-10


Figure 12 31

Figure 12-31


Figure 12 41

Figure 12-41


Lecture 10 thymocyte selection ii

What happens to thymic positive selection if there is an MHC incompatibility between donor and host?


Figure 5 132

Figure 5-13

What happens in a radiation chimera?

Positive selection to host cortical epithelial cells

Radioresistant

host type

Bone marrow derived

Donor type

Negative selection to donor and host MHC


Figure 5 11

Figure 5-11


Positive and negative selection1

Figure 5.12

Positive and Negative selection

Allogeneic chimera experiment: A -> B

Semi-allogeneic chimera experiment: A -> (AxB)F1


Molecular basis of direct allogeneic mhc recognition

Molecular basis of direct allogeneic MHC recognition


Lecture 10 thymocyte selection ii

The importance of eliminating Mature T cells from the bone marrow inoculum before transplant


Figure 12 33

Figure 12-33


Figure 12 34

Figure 12-34


Lecture 10 thymocyte selection ii

Molding of thymocyte repertoire by self MHC + peptides

Double positive

thymocyte

ab

TCR

CD4

CD8

Too strong signal

death by negative selection

No signal

death by neglect

  • Appropriate, weak signal through

  • MHC+self peptide promotes

  • survival

  • loss of irrelevant coreceptor (CD8 or CD4)

  • maturation to helper or killer phenotype


Lecture 10 thymocyte selection ii

Self-tolerance mechanisms in the thymus

(Central tolerance)

  • Cells with high affinity to self (+MHC) are eliminated

  • Problem: The thymus is a relatively small, sequestered organ. How can T cell tolerance be induced to self-proteins produced by other tissues?

  • Three redundant solutions

    • AIRE induced, "ectopic" expression of peripheral antigens in the thymus

    • The generation of regulatory (suppressor) cells

    • Mature T cells are subject to additional tolerance mechanisms (Peripheral tolerance)


Lecture 10 thymocyte selection ii

  • AIRE

  • Mutations of this gene are responsible for the clinical disorder autoimmune polyendocrinopathy syndrome type I

  • Patients develop multiple autoimmune syndromes to endocrine organs, such as parathyroid and adrenal glands.

  • The protein is a transcription factor that is believed to turn on many tissue specific genes IN THYMIC MEDULLARY EPITHELIAL CELLS and plays a role in negative selection.


Figure 13 9 part 1 of 2

Figure 13-9 part 1 of 2

Slide from Janeway book


Figure 13 9 part 2 of 2

Figure 13-9 part 2 of 2

Slide from Janeway book


Lecture 10 thymocyte selection ii

gd T cells also develop in the thymus

THYMUS

CD4

~4%

CD8

Developing T cells with no b chain: including gd


Figure 5 133

Figure 5-13


Figure 5 4

Figure 5-4


Figure 5 9

Figure 5-9


Lecture 10 thymocyte selection ii

Summary of thymocyte development

  • The major pathway of thymocyte development involves ab T cells. The thymus is also necessary for gd T cell development.

  • ab T cell development starts with b gene recombination, expression, and clonal expansion.

  • Cells then recombine TCRa and are screened for positive selection on cortical epithelial cells. Thus "self MHC" is defined by the cortical epithelial cell.

  • Positive selection involves signals initiated with tyrosine phosphorylations that promote directed differentiation.

  • Lymphocytes can be repopulated by bone marrow transplantation.

  • Negative selection occurs in the thymus, where T cells reactive to many self-antigens are expressed on (or by) medullary epithelial cells and other antigen presenting cells.

  • Negative selection can also occur at later developmental stages.


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