BASICS OF IMMUNOLOGY for beginners.pptx

ASICS OF IMMUNOLOGY for beginners.

1. BASICS OF IMMUNOLOGY- PART I

2. DNB QUESTIONS Describe the various sub-types of lymphocytes and discuss the role of T lymphocytes in Transfusion Medicine (5+5) JUNE 2020 Regulatory T cells and their role in immune tolerance (5+5) DEC 2019 a) What are different Subtypes of T lymphocytes? [3] b) Discuss role of T lymphocytes in Transfusion Medicine. [7] DEC 2022 Describe T cell subsets and their clinical significance. [10] JUNE 2022 a) Describe various subtypes of lymphocytes b) Functions of T and B lymphocytes in immune response (5+5) JUNE 2019 a) Regulatory T cells (Tregs) b) Their role in Immune Tolerance (5+5) DEC 2017

3. Contents Overview of haematopoiesis Mechanisms of the immune system: Innate vs Adaptive Immunity T-cell development Positive and Negative Selection Regulatory T-cells T-cell activation T-cell differentiation: T-cell subsets Role of T-lymphocytes in Transfusion Medicine

4. hematopoiesis Self-renewing hematopoietic stem cells give rise to lymphoid and myeloid progenitors

5. ADAPTIVE IMMUNITY There are two types of adaptive immune responses: Humoral immunity - mediated by soluble proteins (antibodies) that are produced by B lymphocytes Cell-mediated or cellular immunity - mediated by T lymphocytes

6. Lymphocytes originate from the common lymphoid progenitor cell in the bone marrow Lymphoid progenitors that mature in the thymus become T-lymphocytes, and those that mature in the bone marrow become B-lymphocytes, Natural Killer (NK) cells, or lymphoid-derived Dendritic cells On encounter with antigen, these immunocompetent T and B lymphocytes undergo blast transformation, usually in the lymph nodes, to form Effector Lymphocytes

7. IMMUNE RESPONSE The lag phase, until an appropriate immune response occurs, is called the latency, pre-seroconversion, or window period Antibody cannot be detected with serologic testing T and B cells are very active in processing antigen and initiating the primary response to the antigen The primary antibodies are the immunoglobulin M (IgM) subclass, whereas the antibodies of the secondary response are the immunoglobulin G (IgG) subclass

8. After the antigen is cleared, memory cells are stored in immune organs of the host When the same antigen is encountered again, the memory cells produce a stronger and more rapid response IgG antibodies are formed during the secondary response IgG secondary antibodies have a higher avidity for antigen and can be produced by much lower concentrations of antigen IMMUNE RESPONSE

9. T-LYMPHOCYTES T lymphocytes are primarily involved in cell-mediated immunity (CMI), which requires interaction among macrophages, dendritic cells (DC), and antigens CMI is independent of antibody production by B lymphocytes There are three important functional subsets of T lymphocytes: Helper T lymphocytes ( Th ) Cytotoxic T lymphocytes (CTL, TC) Regulatory T lymphocytes (Treg)

10. T-cell development T-cell development is divided into two clusters of events: Early thymocyte development : diverse TCR population of immature T cells is generated, and Selection events : depend on TCR interactions so that only those cells that are self-restricted and self-tolerant will leave to populate the periphery Early thymocyte development is T-cell receptor independent and brings cells through uncommitted CD4 CD8 (double negative, DN) stages to the T-cell receptor-expressing, CD4 CD8 (double positive, DP) stage

11. T-cell development The specific events in this early stage include: 1. Commitment of hematopoietic precursors to the T cell lineage, 2. Initiation of antigen receptor gene re-arrangements, and 3. Selection and expansion of cells that have successfully rearranged one of their T-cell receptor genes (selection) The second phase of T-cell development is largely dependent on T-cell receptor interactions and brings cells to maturity from the CD4CD8 (DP) stage to the CD4 or CD8 single positive (SP) stage

12. T-cell development The events in this last phase of development include: 1 . Positive selection : selection for those cells whose T-cell receptors respond to self-MHC, 2. Negative selection : selection against those cells whose T-cell receptors react strongly to self-peptide/MHC combinations, and 3. Lineage commitment, commitment of thymocytes to effector cell lineages, including CD4 helper or CD8 cytotoxic populations

13. Why is thymic selection necessary? Most distinctive property of mature T cells is that they recognize only foreign antigen combined with self-MHC molecules However, randomly generated TCRs will certainly have no inherent affinity for “foreign antigen plus self-MHC molecules.” They could recognize foreign MHC/peptide combinations, which would not be useful, or self-MHC/self-peptide combinations, which could be dangerous Two distinct selection processes are required: Positive selection , which selects for those thymocytes bearing receptors capable of binding self-MHC molecules, resulting in MHC restriction Negative selection , which selects against thymocytes bearing high-affinity receptors for self-MHC/peptide complexes, resulting in self-tolerance Because only self-peptides are presented in the thymus, these two selection processes ensure that surviving thymocytes express TCRs that have low affinity for self-peptides in self-MHC

14. Positive and Negative Selection of Thymocytes in the Thymus DP thymocytes that express new TCR dimers browse the MHC/ peptide complexes expressed by the cortical thymic epithelial cells ( cTECs ) The large majority of DP thymocytes die in the cortex by neglect because of their failure to bind MHC/peptide combinations with sufficient affinity The small percentage whose TCRs bind MHC/peptide with high affinity die by clonal deletion (negative selection) Those DP thymocytes whose receptors bind to MHC/peptide with intermediate affinity are positively selected and mature to single positive (CD4 or CD8) T lymphocytes

15. These migrate to the medulla, where they are exposed to AIRE medullary thymic epithelial cells ( mTECs ), which express tissue-specific antigens and can mediate negative selection Medullary dendritic cells can acquire mTEC antigens by engulfing mTECs , and mediate negative selection (particularly of MHC Class II restricted CD4 thymocytes) Positive and Negative Selection of Thymocytes in the Thymus

16. Relationship between TCR affinity and selection Fewer than 5% of thymocytes produce TCRs that bind to MHC/peptide complexes with high affinity Most of these will be deleted by negative selection (some will become regulatory T cells and other specialized cell types) More than 90% generate TCRs that either do not bind to MHC/ peptide complexes or bind them with very low affinity, these die by neglect Fewer than 5% generate TCRs that bind with just the right intermediate affinity to self-MHC/peptide complexes, these will survive and mature

17. Regulatory T cells (TREG cells) Treg cells can inhibit the proliferation of other T-cell populations, thus suppressing auto-reactive immune responses They express on their surface CD4 as well as CD25, the  chain of the IL-2 receptor TREG cells express a master transcriptional regulator, FoxP3, the expression of which is necessary and sufficient to induce differentiation to the TREG lineage. TREG cells can develop in the thymus and appear to represent an alternative fate for autoreactive T cells

18. mechanisms of TREG activity Cytokine deprivation : TREGs express relatively high levels of high-affinity IL-2 receptors and can compete for the cytokines that activated T cells need to survive and proliferate Cytokine inhibition : TREGs secrete cytokines, including IL-10 and TGF- β , which bind receptors on activated T cells and reduce signaling activity Inhibition of antigen presenting cells: TREGs can interact directly with MHC Class II expressing antigen-presenting cells and inhibit their maturation, leaving them less able to activate T cells Cytotoxicity: TREGs can also display cytotoxic function and kill cells by secreting perforin and granzyme

19. T-cell activation AND DIFFERENTIATION Activation of a naïve T cell in a secondary lymphoid organ results in the generation of effector and memory T cells Effector CD4 T cells become helper T cells (TH) and secrete cytokines that enhance the activity of many other immune cells Effector CD8 T cells are cytotoxic cells (TC) that kill infected cells

20. Differences in the properties of professional APCs that induce T-cell activation

21. Dendritic cells are the best activators of naïve T cells; have relatively high levels of expression of MHC and costimulatory molecules when they are mature and activated Activated B cells interact most efficiently with differentiated TH cells that are specific for the same antigen that activated them Macrophages act in secondary lymphoid tissues (SLOs) as well as interact with effector cells in the periphery

22. T cell differentiation In 1 to 2 days after successful engagement with a dendritic cell in the T-cell zone of a secondary lymphoid organ, a naïve T cell will enlarge into a blast cell and begin undergoing repeated rounds of cell division Activated T cells divide 2 to 3 times per day for 4 to 5 days, generating a clone of progeny cells that differentiate into memory and effector T-cell populations Activated T cells and their progeny gain unique functional abilities, becoming effector helper or cytotoxic T cells that indirectly and directly act to clear pathogen CD8+ cytotoxic T cells leave the secondary lymphoid tissues and circulate to sites of infection where they bind and kill infected cells CD4 helper T cells secrete cytokines that orchestrate the activity of several other cell types, including B cells, macrophages, and other T cells

23. Regulation and function of T-helper subtypes

24. Role of t-lymphocytes in transfusion medicine T-lymphocytes As The Reservoir Of Retroviruses Transmitted By Transfusion The primary cellular target for HIV-1 infection is the CD4 T-lymphocyte, which serves a helper/ inducer role in regulating immune responses CD4 T cells are also the primary cells involved in cell-mediated immunity against a variety of pathogens ( eg , Mycobacterium organisms) CD4 T lymphocytes can also harbor and transmit human T-cell lymphotropic virus ( HTLV ), a retrovirus distantly related to HIV-1

25. Role of lymphocyte in adverse transfusion reaction TA-GVHD Transfusion related immunomodulation (TRIM): Down regulation of immune responses due to the transfusion of allogeneic blood products resulting in the recipient being exposed to large amounts of foreign antigens (allo-antigens) Role of t-lymphocytes in transfusion medicine

26. Pathophysiology of TA-GVHD in Immunocompromised

27. T-cell-mediated rejection (TCMR) of transplanted organ: Recipient immune cells recognize donor MHC molecules either by direct presentation (donor-derived APCs present alloantigens to recipient T cells) or indirect presentation (recipient APCs capture alloantigen and present them to T cells) CD4+ helper T cells cause interstitial inflammation in the graft, and CD8+ cytotoxic T cells cause tubulitis and vasculitis Morphologic features of acute TCMR include interstitial inflammation, tubulitis , and intimal arteritis Role of t-lymphocytes in transfusion medicine

28. Lymphocytes as cellular therapies: Donor Lymphocyte Infusion : The goal of DLI is remission of cancer by a process called the graft-versus-tumor effect (GVT),where the donor T-cells attack and control the growth of residual cancer cells CAR-T cell Therapy : T cells are taken from the patient's blood and are changed in the lab by adding a gene for a receptor (called a  chimeric antigen receptor  or  CAR ), which helps the T cells attach to a specific cancer cell antigen. The CAR T cells are then given back to the patient Role of t-lymphocytes in transfusion medicine

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