T Cell Differentiation Ned Braunstein, MD. Whether or not an individual makes an immune response to a particular antigen depends on what MHC alleles an.

Slides:



Advertisements
Similar presentations
Self/Non-Self Recognition
Advertisements

Lecture 10 Thymocyte selection II
Chapter 8 B/T cell development B T. Adaptive immunity B/T cells Innate immunity BCR/TCR: epitope recognition Gene rearrangement of AgR Pattern recognition.
Diagnostic Immunology Topic: Immunological Tolerance Objectives: Define Immunological tolerance Define Immunological tolerance Discuss mechanism of tolerance.
The Immunological Orchestra Richard Gershon, Maestro
Dental Microbiology #211 IMMUNOLOGY 2006 Lecture 3.
Transcomplementation can result from the combination in trans of  and  chains encoded by MHC class II genes on different chromosomes. Inter-isotypic.
Lecture 8 The Development of Lymphocytes. Core content.
Lymphocyte development and survival Chapter 7. Objectives Describe or construct flow charts showing the stages in development of B cells and T cells,
Lecture 9- T cell development Flow cytometry- how it works Thymic architecture and cells Thymic development I- generation of a TCR  chain Thymic development.
T cell Development. Basic Principles of T Cell Development Each cell randomly rearranges a specific TCR. The presence of the pMHC epitope, stage of development.
Lecture 3 clinical immunology Antigen Presenting Cells
Antibody structure Heavy chain constant region determines antibody class.
Antigen Recognition by T Lymphocytes
Principles of Immunology T Cell Development 3/14/06 “For every problem there is a neat, simple solution, and it is always wrong. “ H L Mencken.
Introduction to C.M.I., the TCR, and T Cell Development web Abbas Chapters 7,8.
T-cell receptor Complex: TCR + CD3  and  result from differential RNA splicing Immunoreceptor tyrosine-based activation motif.
V  -J . T Cell Maturation in the Thymus Positive selection: permits the survival of only those T cells whose TCRs are capable of recognizing self-MHC.
Chapter 5 Understand how the thymus is the site of development for T cells How do cells commit to a lineage during T cell development How do we eliminate.
T Cell Development Amy Lovett-Racke, PhD Associate Professor
Generation of antibodies and T cell receptors by V(D)J recombination Lymphocyte development: generation of cells with functional and useful antigen receptors.
T Cell Development ? ? ? ?? ? ?. Role of the thymus in T cell development Required for T cell development –Neonatal thymectomy –Nude mice Shapes T cell.
Introduction to Autoimmunity Alon Monsonego, Ph.D. The department of Microbiology and Immunology Tel:
Chapter 10 T-cell Maturation, Activation, and Differentiation
1101/20/98 Major Histocompatability Complex Molecular chaparones Hugh B. Fackrell.
Chapter 10 T-Cell Maturation, Activation, and Differentiation.
Tolerance & Autoimmunity
DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS.
DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS.
T lymphocytes Jianzhong Chen, Ph. D. Institute of Immunology, ZJU.
Immune Regulation and Tolerance
T-cell development central tolerance. The cellular organization of the thymus.
Chapter 7 Major Histocomptibility Complex (MHC).
Lymphocyte Development & Generation of Lymphocyte Antigen Receptors Pin Ling ( 凌 斌 ), Ph.D. ext 5632; References: 1. Abbas, A,
Tolerance Specific negative immunity Not the same as immunosuppression, which is non-specific 3 Tolerance mechanisms: Clonal deletion: Loss of certain.
Evgeniya Solodova Introduction: Regulatory cytokine transforming growth factor-β (TGF-β): - - is a secreted protein that exists in three isoforms.
Basic Immunology.
Specific Defenses of the Host
1. Repetition is good, especially in different contexts. 2. As good students, you are accustomed to mastering “the syllabus.” At least in this course,
Statistical physics of T cell receptor selection and function Thesis committee meeting, 04/15/2009 Andrej Košmrlj Physics Department Massachusetts Institute.
Asilmi 08 - T CELL DEVELOPMENT TODAY T LYMPHOCYTE DEVELOPMENT.
Lecture #10 Aims Describe T cell maturation and be able to differentiate naïve and effector T cells. Differentiate the development and functions of Th1.
Germline-encoded receptors Gene rearranged receptors: TCR/BCR Ags………. Innate immunity Adaptive immunity B/T cells Pattern recognition Epitope recognition.
This will be covered later in the course and is presented here to provide context to understanding isotype switching. It will not to be tested in Exam.
Antigen Presentation/Cell cooperation in Antibody response Pin Ling ( 凌 斌 ), Ph.D. ext 5632; References: 1. Male D., J. Brostoff,
The development of lymphocytes
IMMUNOLOGICAL TOLERANCE Lecture 6 Jan Żeromski 2007/2008.
T Cell Ontogeny Takes place in the thymus Progenitor cells from the BM arrive at cortico-medullary junction Migrate to subcapsular region, begin to differentiate.
Immunological tolerance. Definition: Unresponsiveness to a given antigen induced by the interaction of that antigen with the lymphocytes; Antigen specific!!!
T-Cell Maturation, Activation, And Differentiation W. Robert Fleischmann, Ph.D. Department of Urologic Surgery University of Minnesota Medical School
In unimmunized mice: 1 in 26,300 spleen B cells could make anti-SRC IgM no detectable (
Attribution: University of Michigan Medical School, Department of Microbiology and Immunology License: Unless otherwise noted, this material is made available.
DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS.
T-Cell Maturation, Activation, and Differentiation
Chapter 13 Lymphocyte Maturation and Antigen Receptor Expression
Chapter 15.  Immunological tolerance is defined as unresponsiveness to an antigen that is induced by previous exposure to that antigen  Antigens that.
IMMUNOLOGICAL TOLERANCE. BASIC FACTS ABOUT TOLERANCE Tolerance – a state of unresponsiveness specific for a given antigen It is specific (negative) immune.
Chapter 8 The Development and Survival of Lymphocytes.
Lecture Outline Antigens Definition Exogenous Endogenous
T Cell Development in the Thymus David Straus
T-cell development in the thymus
Biology of T cells The individual has an enormous number of different T cells. Each T cell bears a unique, clonally distributed receptor for antigen, known.
Development of B and T lymphocytes
Overview B cell development T cell development Topics 11/7/2018
Chapter 9 T-cell Development
Tolerance.
T cell development.
Cellular Mechanisms of Fatal Early-Onset Autoimmunity in Mice with the T Cell-Specific Targeting of Transforming Growth Factor-β Receptor  Julien C. Marie,
Development of B and T lymphocytes
Regulatory T Cells and Immune Tolerance
Presentation transcript:

T Cell Differentiation Ned Braunstein, MD

Whether or not an individual makes an immune response to a particular antigen depends on what MHC alleles an individual has. Example – Hepatitis vaccination Example – autoimmune disease – eg: RA Concept – Ir genes

MHC genes control immune responsiveness in 2 ways: Peripheral effects – peptide binding Central effects – repertoire selection in thymus Mechanisms – Ir genes

What happens in the thymus? Ordered TCR gene rearrangement and TCR expression Ordered expression of surface molecules: CD2 CD4 and CD8 CD3 and the TCR Thymocyte Education: Selection of the T cell repertoire Negative Selection Positive Selection

CD3 pT  CD2 TCR  CD2 CD3 CD2 TCR  CD8 CD4 CD3 CD2 TCR  CD4 CD3 CD2 TCR  CD8 CD3 CD2 TCR  TCR  Pathway Differentiation Pathways in the Thymus TCR  Pathway CD4 T cell CD8 T cell

CD3 pT  CD2 TCR  CD2 CD8 CD4 CD3 CD2 TCR  Differentiation of  T cells in the Thymus TCR  D –> JV –> D –> J V –> D –> J TCR  germlinegermlineV –> J Surface Molecule Expression TCR gene rearrangements

CD4 Staining CD8 Staining CD4-CD8-CD4+CD8- CD4+CD8+CD4-CD8+ 3% 5%80% 12% TCR repertoire selection and thymocyte differentiation into CD4+ or CD8+ T cells

CD8 CD4 CD3 CD2 TCR  CD4 CD3 CD2 TCR  CD8 CD3 CD2 TCR  CD4 T cell CD8 T cell Thymic epithelial or dendritic cell Class II MHC/peptide Class I MHC Thymic epithelial or dendritic cell Thymic selection of the TCR repertoire TCR repertoire selection and thymocyte differentiation into CD4+ or CD8+ T cells

Interaction of the TCR expressed on CD4+, CD8+ (double positive) thymocytes with MHC class I/peptide complexes or MHC class II/peptide complexes expressed on thymic epithelial or dendritic cells selects the TCR repertoire and dictates differentiation into either CD4+ or CD8+ (single positive) T cells High affinity Interactions of the TCR with MHC/peptide complexes leads to thymic cell apoptosis and death; very low affinity interactions does not give sufficient signals for differentiation and these thymocytes also die. The only double positive thymocytes that survive and further differentiate into CD4+ or CD8+ T cells are cells with TCRs which interact with intermediate affinity to epithelial or dendritic cell MHC/peptide complexes. TCR repertoire selection and differentiation into CD4+ or CD8+ T cells

High Affinity Low AffinityIntermediate Affinity Apoptosis Negative Selection Death Growth Positive Selection No Growth No Selection Death Affinity of the interaction between TCR and the MHC/self-peptide complex dictates thymic selection

Questions How can we demonstrate that the MHC molecules in the thymus determine the repertoire of T cells that develop in the thymus? Bone marrow chimera experiments TCR transgenic mice

Bone Marrow Chimeric Animals Irradiate host animal (1) and reconstitute with bone marrow from donor animal (2) T cells and APCs (B cells, DCs, macrophages) express MHC of the donor (2) Other cells (eg: thymic epithelium) express MHC of the host (2)

Question Is the T cell repertoire determined by MHC genes expressed by bone marrow-derived cells or is it determined by MHC genes expressed in thymus?

*Strain A and Stain B are highly inbred congenic mouse strains that differ only at the MHC allele expressed; A or B Thymic education: MHC genotype of host thymus determines the Immune response (Ir) repertoire of T cells

Use of TCR Transgenic Animals to Study Thymic Selection Clone the rearranged TCR  and  genes from a T cell. Inject the rearranged TCR genes into a fertilized egg from a mouse that has mutant rag genes. The mouse cannot rearrange its own TCR genes. All developing thymocytes will therefore express this TCR. Study how alterations in the thymic environment (different MHC genes or peptides) change the developmental fate of this T cell

The 2C cell line 1.CD8 positive 2.Specific for the "H-Y" antigen This antigen is a peptide derived from some molecule encoded on the Y chromosome 3.Derived from a femaleH-2 b mouse 4. Restricted by D b CD8 CD3 CD2 2C TCR  CD8 T cell by immunization with male cells

Question If we clone the DNA encoding the 2C TCR  and inject the genes into eggs from H-2 b mice, what happens to the T cells as they develop in the thymus of female mice? (Since the 2C T cell came from a CD8+ T cell in a female H-2b mouse, we would expect that the T cells should mature in the thymus and at least some would mature into CD8+ T cells. Do they all become CD8+ or do some also become CD4+?)

CD4 Staining CD8 Staining CD4-CD8-CD4+CD8- CD4+CD8+CD4-CD8+ 3% 5%80% 12% Thymocyte differentiation into CD4+ or CD8+ T cells in normal mouse

CD4 Staining CD8 Staining CD4-CD8-CD4+CD8- CD4+CD8+CD4-CD8+ 3% 15%80% 2% Positive Selection: Differentiation of 2C TCR Tg’ic Thymocytes in Female H-2 b mouse

Question If we clone the DNA encoding the 2C TCR  and inject the genes into eggs from H-2 b mice, what happens to the T cells as they develop in the thymus of male mice? (Since the CD8+ 2C T cell responds to male cells from H-2 b mice, we would expect that no CD8+ T cells mature. Do any CD4+ T cells mature?)

CD4 Staining CD8 Staining CD4-CD8-CD4+CD8- CD4+CD8+CD4-CD8+ 3% 2%93% 2% Negative Selection: No Differentiation of 2C TCR Tg’ic Thymocytes in Male H-2 b mouse

Question If we clone the DNA encoding the 2C TCR  and inject the genes into eggs from H-2 k mice, what happens to the T cells as they develop in the thymus of female mice?

CD4 Staining CD8 Staining CD4-CD8-CD4+CD8- CD4+CD8+CD4-CD8+ 3% 2%93% 2% Absence of Positive Selection: No Differentiation of 2C TCR Tg’ic Thymocytes in Female H-2 k mouse

Question Is the absence of maturation beyond double-positive stage in H-2 k mice due to negative selection or positive selection?

CD4 Staining CD8 Staining CD4-CD8-CD4+CD8- CD4+CD8+CD4-CD8+ 3% 15%80% 2% Positive Selection: Normal Differentiation of 2C TCR Tg’ic Thymocytes in Female H-2 bxk mouse

Individuals with different MHCs have different TCR repertoires T cells mature into CD4 or CD8 single-positive cells as a result of positive selection. Implications of Positive/Negative Selection