Presentation is loading. Please wait.

Presentation is loading. Please wait.

Lecture 10 Thymocyte selection II Thymocyte positive selection A word about signaling Demonstration in radiation bone marrow chimeras Implications for.

Similar presentations


Presentation on theme: "Lecture 10 Thymocyte selection II Thymocyte positive selection A word about signaling Demonstration in radiation bone marrow chimeras Implications for."— Presentation transcript:

1 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  T cells

2 Positive and Negative Selection The thymus: Selects the useful Ignores the useless Removes the harmful Positive Selection Death by neglect Negative selection

3 Figure 5-12 part 1 of 2 CD8 CD4  TCR CD8 T cell CD4 T cell

4 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) pT  deficientFew  T cells No thymus (DiGeorge)No T mature cells No thymocytes (ADA - )No T mature cells

5 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.

6 Figure 6-16

7 Figure 5-13

8 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.

9 Cells of the immune system Thymus Adaptive Innate Naïve, resting lymphocytes in lymph nodes, spleen Bone marrow/fetal liver

10 Figure 5-10

11 Figure 5-12 part 1 of 2 CD8 CD4  TCR

12 Figure 5-13 Radioresistant host type What happens in a radiation chimera? Positive selection to host cortical epithelial cells Bone marrow derived Donor type Negative selection to donor and host MHC

13 AXB A B Host type controls MHC restriction of T cell repertoire

14 Development of Major Histocompatibility Complex Restriction Patterns in Bone Marrow Plus Thymic Chimeras See next slide for explanation

15 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.

16 Figure 5-10

17 Figure 12-31

18 Figure 12-41

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

20 Figure 5-13 Radioresistant host type What happens in a radiation chimera? Positive selection to host cortical epithelial cells Bone marrow derived Donor type Negative selection to donor and host MHC

21 Figure 5-11

22 Positive and Negative selection Allogeneic chimera experiment: A -> B Semi- allogeneic chimera experiment: A -> (AxB)F1 Figure 5.12

23 Molecular basis of direct allogeneic MHC recognition

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

25 Figure 12-33

26 Figure 12-34

27  TCR CD4 CD8 Double positive thymocyte No signal death by neglect Too strong signal death by negative selection Appropriate, weak signal through MHC+self peptide promotes survival loss of irrelevant coreceptor (CD8 or CD4) maturation to helper or killer phenotype Molding of thymocyte repertoire by self MHC + peptides

28 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)

29 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.

30 Figure 13-9 part 1 of 2 Slide from Janeway book

31 Figure 13-9 part 2 of 2 Slide from Janeway book

32 CD4 CD8 THYMUS Developing T cells with no  chain: including  ~4%  T cells also develop in the thymus

33 Figure 5-13

34 Figure 5-4

35 Figure 5-9

36 Summary of thymocyte development The major pathway of thymocyte development involves  T cells. The thymus is also necessary for  T cell development.  T cell development starts with  gene recombination, expression, and clonal expansion. Cells then recombine TCR  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.


Download ppt "Lecture 10 Thymocyte selection II Thymocyte positive selection A word about signaling Demonstration in radiation bone marrow chimeras Implications for."

Similar presentations


Ads by Google