Shiv Pillai Ragon Institute, Massachusetts General Hospital Harvard Medical School

Transcription

1 CTLs, Natural Killers and NKTs 1 Shiv Pillai Ragon Institute, Massachusetts General Hospital Harvard Medical School

2 CTL inducing tumor apoptosis

3 3 Lecture outline CD8 + Cytotoxic T lymphocytes (CTL) Activation/differentiation Mechanisms of killing CTLs and disease Natural Killer Cells (NK) Functions Activating and inhibitory receptors Natural Killer T cells (NKT) and other CD1 restricted T cells (non-nkt)

4 Major Roles of CD8 + CTLs in Defense and Disease 4 Defense against viral infections Defense against bacteria and fungi that resist phagosomal destruction Immune surveillance of tumors Autoimmune attack on self tissues Allograft rejection

5 Class I MHC Pathway of Antigen Presentation Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

6 Cross-presentation of ingested antigens allows CD8+ T cell activation Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

7 Cross-Presentation of Antigens to CD8 + T cells How do naive T cells specific for a virus that does not infect DCs get activated? Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 Copyright by Saunders, 2011 by Saunders, an imprint an imprint of of Elsevier Inc. Inc.

8 Remarkable Expansion of CD8+ T cells Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

9 How CD4 + T Cells Help CD8 + T Cells Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

10 Steps in CTL-Mediated Lysis of Target Cells Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

11 Conjugates Between CTLs and Target Cells (1) Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

12 Mechanisms of CTL Killing of Target cells Granzyme B cleaves after aspartates activates caspases Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

13 CTL-Mediated Tissue Injury: Acute Viral Hepatitis (HBV, HCV)

14 CD8 T cells become Exhausted During Chronic Viral Infection Exhausted T cells in chronic infections with LCMV, HIV, HBV, HCV Zajac et al., JEM 1998 Wherry et al., J. Vir. 2003

15 The PD-1 pathway is an important therapeutic target PD-1 pathway has been exploited by microbes and tumors to evade immune eradication PD-1/PD-L Pathway contributes to functional T cell exhaustion during chronic infection and cancer

16 Vivier et al. Science 2011 NK Cells

17 NK Cells Kill Injured and Infected Cells Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

18 Immune Responses Against Viruses Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 Copyright by Saunders, 2011 by an an imprint of of Elsevier Elsevie Inc.

19 NK cells - What are they? Human CD3-,CD56+, (Nkp46+) Mouse CD3-,NKR-P1C+ (aka NK1.1), (NKp46+) Part of the Innate Lymphoid Cell 1 class (ILC1 cells) Function in innate immunity to protect against viruses, bacteria, & tumors Produce cytokines & kill abnormal cells From Lewis Lanier

20 NK Cells NK cell progenitors in bone marrow Thymus not required. Do not rearrange TCR or Ig genes 5-20% peripheral blood lymphocytes 5% lymphocytes in spleen, abundant in liver, 70% of the lymphocytes in decidual tissue From Lewis Lanier

21 NK Cells - What do they do? Cell mediated-cytotoxicity natural killing Antibody-dependent cellular cytotoxicity (ADCC) Kill using Granzymes and perforin Early g-interferon production Secretion of other cytokines: TNFa, LTa, GM-CSF, IL-5, M-CSF, IL-3, IL-10, IL-13, MIP-1a, MIP-1b, RANTES, etc. From Lewis Lanier

22 NK cell Functions Augmented by **Interferon-a/b Cytokines augments cytolytic activity **IL-15 required for development, induces proliferation, increases cytotoxicity **IL-12 & IL-18 IL-2 augments INF-g production induces proliferation, increases cytotoxicity physiological relevance? From Lewis Lanier

23 NK cells like to kill cells lacking MHC class I missing self Karre et al Nature 319:675

24 BBalancing activation and Inhibition ViVivier et al. Science 2011

25 Activating and Inhibitory NK Cell Receptors Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

26 Activating and Inhibitory NK Cell Receptors Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

27 Activating and Inhibitory NK Cell Receptors Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

28 Activating NK Cell Receptors Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

29 Inhibitory NK Cell Receptors Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

30 ADCC- Antibody Dependent Cellular Cytotoxicity 30

31 NK Cells Activate Macrophages Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7 th edition. Copyright 2011 by Copyright Saunders, 2011 by an Saunders, imprint an imprint of Elsevier of Inc.

32 Evidence that NK cells are important in viral immunity in humans and mice Severe Epstein-Barr virus infection in rare patients lacking NK cell function Severe herpesvirus infections in rare pateints without Natural Killer cells. Natural Killer cell depletion enhances virus synthesis and virus-induced hepatitis in vivo. From Lewis Lanier

33 KIR in Hematopoietic Stem Cell Transplantation Detrimental effects grafted allogeneic stem cell rejection by host NK cells Beneficial effects - in leukemia patients given an allogeneic bone marrow graft ---- graft vs. leukemia activity arising donor NK cells kill residual host leukemia cells From Lewis Lanier

34 NKT cells: a subset of CD1 restricted T cells TThThey are NOT NK cells

35 NKT cells: a subset of CD1 restricted T cells that recognize lipid-linked antigens T cells expressing an invariant TcRa chain and recognizing lipid antigens presented by CD1d In humans numerous non-nkt T CD4+ T cells exist that are CD1a, CD1b, and CD1c restricted these cells respond to lipid antigens from mycobacteria etc.

36 NKT cells bridge innate and adaptive immunity and amplify the innate immune response by rapidly producing cytokines Pathogen Innate Immunity NKT cells Adaptive Immunity Minutes Hours Days From Lewis Lanier

37