T cells in health and rheumatic diseases -Sheraton Hotel, Ankara, 13 March 2009 The T side of the immune system - an overview; novel functions of T cells Andrew P. Cope MD PhD Arthritis Research Campaign Professor of Rheumatology Academic Department of Rheumatology Division of Immunology, Infection and Inflammatory Diseases King s College School of Medicine King s College London andrew.cope@kcl.ac.uk
1. What is the immune system for..? The immune system exists to protect the host from foreign pathogens. The first line of defence innate immunity is an ancient system which has evolved from invertebrates. Vertebrates have developed an adaptive immune system through the acquisition of RAG genes. Inherited defects in adaptive immunity are common. Defects in innate immunity are rare, and were lethal in the pre-antibiotic era.
Innate and adaptive immunity Property Innate immune system Adaptive immune system Receptors Fixed in genome Encoded in gene segments Rearrangement not necessary Rearrangement necessary Distribution Non-clonal Clonal All cells of a class identical All cells of a class distinct Recognition Conserved molecular patterns Details of molecular structure (LPS, glycans, nucleic acid) (proteins, peptides, -CHO-) Self/non-self Perfect: selected over Imperfect: selected in discrimination evolutionary time individual somatic cells Action time Immediate activation Delayed activation of effectors Response Co-stimulation Clonal expansion or anergy Cytokines IL-2 Chemokines Effectorcytokines (IL-4, IFNγ)
2. How are the two immune systems related? The innate immune system watches out for pathogenic organisms. Adaptive immunity serves to generate an effective response to pathogens that overcome the innate immune response. This allows for - delay tactics -specificity control -memory -appropriate induction of inflammatory mediators Both immune systems can switch each other off
3. What happens when adaptive immunity goes wrong? Aberrant adaptive immune responses promote: (1) Allergic immune responses (2) Rejection of tissue allografts (3) Autoimmunity and autoimmune disease
Overview of lecture 1. Where do T cells come from? 2. What do T cells see? 3. How do they respond? 4. What do T cells do? 5. How are T cell responses regulated? 6. Prospects for the future?
Post-natal thymict cell development CXCR4, CCR7 CCR9 2 3 1. T cell precursors enter thymus, and migrate to cortex as DN CD4 - CD8 - thymocytes 2. Pre-TCR mediated selection 3. DN mature into DP CD4 + CD8 + thymocytes in cortex 1 5 S1PR CCR7 4 4. Positive selection of DP thymocytes promotes maturation to SP thymocytes that migrate back to medulla 5. SP cells leave thymus for periphery
Specificity of CD4 + and CD8 + T cells CD8 + T CTL CD4 + T helper CD8 + CD4 + TCR CD8 coreceptor MHC class I/class II CD4 coreceptor APC APC
Post-natal thymict cell development CXCR4, CCR7 CCR9 2 3 TEC thymic epithelial cell LTi lymphoid tissue inducer cells AIRE autoimmune regulator AIRE+ mtec 1 CCR7 4 LTi 5 S1PR
T cell priming in secondary lymphoid organs afferent lymphatic vessel Lymph Node primary follicle subcapsularsinus HEV T cell Resting B cell Germinal Center B cell Macrophage Myeloid DC Follicular DC Lymphoid DC medullarysinus germinal center efferent lymphatic vessel
Overview of lecture 1. Where do T cells come from? 2. What do T cells see?
TISSUE Anatomy of T cell activation CELLS MOLECULES T T cell DC dendritic cell Lymphoid organs T cell-antigen presenting cell interactions The immunological synapse
The molecular basis of antigen recognition MHC-peptide complex MHC-peptide complex T antigenic peptide alpha helix DRb chain DC a view from the top a view from the side
A Engaging TCR at the cell surface the synapse B c-smac 15nm p-smac 42nm d-smac adapted from Huppa and Davis, Nat Rev Immunol 2003
The mature immunological synapse T cell ligand LFA-1 TCR CD28 c-smac p-smac ICAM-1 MHC CD80/86 overlay lipid bilayer adapted from Bromley et al, AnnuRev Immunol 2001
Synapse formation in CD4 + and CD8 + T cells is different synapse is long-lasting adapted from Huppa and Davis, Nat Rev Immunol 2003 synapse is transient
Overview of lecture 1. Where do T cells come from? 2. What do T cells see? 3. How do they respond?
Detection of early T cell activation events light microscopy confocal microscopy tyrosine phosphorylation
Detection of productive T cell activation M2 M1 MHC-peptide CFSE CD69 CD8 CFSE dilution flow cytometry tetramer technology
The molecular basis of T cell activation receptor module PTK kinase module adaptor module adaptors substrate ATP P substrate P PTP phosphatase module OUTPUT EFFECTOR MODULES OUTPUT proliferation differentiation gene expression mrna processing MAPK NF-kB Ca 2+ lipid kinases caspases cell fate cell communication cytoskeletalchanges migration nucleus
T cell activation at the genome level gene expression profiling
The anatomy of costimulation adapted from Acutoand Michel, Nat Rev Immunol 2003
CD28 quantitative support for TCR signals adapted from Sharpe and Freeman, Nat Rev Immunol 2002
Overview of lecture 1. Where do T cells come from? 2. What do T cells see? 3. How do they respond? 4. What do T cells do?
T cell effectorfunctions -for host defense secrete effector molecules help for B cells eg IgG production contact dependant responses Effector T cell help for other cell subsets eg CTL kill regulate How can T cells deal with the universe of pathogens?
Instructive models of T helper cell differentiation DC IL-12Rb1/2 IL-12/STAT4 IL-12R IL-18R T H T H T H 1 IFNg, TNF + pathogen IFNg, STAT1 T-bet T-bet IFNg remodelling CXCR3 IFNg CCR5 IL-23R T H p IL-2 + pathogen IL-12Rb1 T IL-4R DC TGFb, IL-6, IL-21 RORgt, RORa, STAT3 IL-4, STAT6 GATA-3 T H T H T H 17 ROR IL-17 remodelling T H T H T H 2 IL-4R/STAT6 GATA-3 IL-4 remodelling IL-21, IL-23 (IL-1, TNF) Bcl6 IL-21 CCR3 IL-4 T FH CRTH2 ICOS T FH CCR6 CCR4 IL-17, IL-22 IL-21 IL-4, IL-5, IL-13 IL-10, IL-21 CXCR5 initiation commitment effector
IL-12R IL-18R T H T H 1 IFNg, TNF CXCR3 CCR5 CCR3 CRTH2 T H T H 2 IL-4, IL-5, IL-13 IMMUNITY MEDIATED BY T H SUBSET Host defence to intracellular pathogens (IFNγ, TNF) induction of MHC class II, inos, free radicals Intracellular pathogens; Listeria, Mycobacterium, Toxoplasma, anti-viral immunity Host defence to parasites (IL-4, IL-5, IL-13) Extracellular parasites; intestinal helminths, Leishmania MФ Eos IL-23R T H T H 17 CCR6 CCR4 IL-17, IL-21, IL-22 granulopoiesisand PMN trafficking (IL-17) immune barrier functions (IL-22) Extracellular pathogens: Propionibacterium, Klebsiella, Bacteroides, Candida spp PMN ICOS, CD40L T FH T FH IL-10, IL-21 CXCR5 pivotal for B cell help -differentiation (IL-21); T H skew the germinal centre T cell in lymphoid tissues T-dependent B cell responses: Pneumococcus, Tetanus, Hepatitis virus spp B
Overview of lecture 1. Where do T cells come from? 2. What do T cells see? 3. How do they respond? 4. What do T cells do? 5. How are T cell responses regulated?
Mechanisms of immunological tolerance to self self Ly Ly deletion (apoptosis) self Ly Ly inactivation (anergy) self Ly Ly active suppression S S
Characteristics of CD4 + CD25 high Tregs TCR MHC class II DC CD80/CD86 function resides in CD25 high population suppress proliferation suppress cytokine production of blocking IL-2 gene transcription CD45RO + CD45RA - CTLA4 GITR CD71 CD69 neg HLA-DR neuropilin CTLA4 CD62L + CD103 CD127 lo highly differentiated diverse TCR repertoire anergicto TCR stim. require TCR signal to suppress suppressor function declines with time CD4 + CD25 high
Foxp3 a master control gene for CD4 + CD25 + Tregs forkhead/winged-helix protein scurfin N PRD ZF Zip FKH N L S C X-linked recessive inflammatory disease in scurfy mice Foxp3 deficient mice develop scurfy-like inflammatory disease (prevented by Tregs) IL-2R Foxp3 + stably expressed at high levels by Tregs X-linked recessive IPEX disease in man: autoimmune disease IBD, allergy CD4 + CD25 + Foxp3 transgenesis converts CD4 + CD25 - T cells to Treg-like cells Bennet et al, 2001 Nat Genet 27:20; Brunkow et al, 2001 Nat Genet 27:68
Initiation of adaptive immunity Th cells ON Tregs OFF Treg Treg Teff Teff Teff Teff Teff Teff Teff
Dynamics of immune regulation in adaptive immunity evolving Teff resolving immune response T eff immune response IL-2
Dynamics of immune regulation in adaptive immunity evolving Teff resolving immune response T eff immune response off on high affinity antigen IL-2 +++ IL-2 + strong TCR signal suppressor function cell death costimulation fl costimulatio inflammation and danger egtlr2, IL-6
Generation of inducible regulatory T cell subsets evolving Teff resolving immune response T eff immune response environmental cues: IL-4, IL-10, TGFb idc CD40/CD40L blockade vitamin D3, oestrogen steroids antigen (DAMPS) Th2 Tr1 Th3 IL-4, IL-5, IL-13 IL-10, TGFb, IFNg, IL-5 TGFb
Overview of lecture 1. Where do T cells come from? 2. What do T cells see? 3. How do they respond? 4. What do T cells do? 5. How are T cell responses regulated? How s my immune system, Professor Cope?
SemihSakmar A visit to the Anatolian Civilisations Museum T cells T