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Regulation of immune responses by T cells Costimulation, Th1/Th2, Th17, Th9, Th22, Tregs of all sorts Feb 21 2012

Regulation of immune responses by T cells Costimulation, Th1/Th2, Th17, Th9, Th22, Tregs of all sorts Feb 21 2012 . Today’s Objectives: Be able to describe the need for , and mechanisms of costimulation in T and B cell activation

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Regulation of immune responses by T cells Costimulation, Th1/Th2, Th17, Th9, Th22, Tregs of all sorts Feb 21 2012

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  1. Regulation of immune responses by T cellsCostimulation, Th1/Th2, Th17, Th9, Th22, Tregs of all sorts Feb 21 2012 • Today’s Objectives: • Be able to describe the need for , and mechanisms of costimulation in T and B cell activation • Review the assets, liabilities and unresolved issues of the Th1/Th2 model of immune regulation—integrate newly described cell types Th17, Th9 , Th22 into your knowledge base . Be able to synthesize information on emerging and current T cell subsets • Review the assets, liabilities and unanswered questions concerning the putative roles of regulatory T cell types • Consider how these models of immune regulation can be integrated to give a global picture of immune regulation • Optional: Self study (slides provided) Obtain an overview of the impact of external modifiers such as diet, age or trauma on immune regulation

  2. Before we get started, as a refresher, and to assess your prior knowledge level, you tell me: • Mature naïve T cell needs what to get activated? • Does a resting mature T cell need anything to survive? • What’s a Th2? A Th9? What determines what a T cell “becomes”? • How do co-stimulatory molecules differ from each other (big picture)

  3. 1. Initial contact 2. Stabilization 3. Naive T:DC unique Most steps can happen with multiple cell types, DCSIGN is DC/naïve T specific. Activ’n or Dissoc’n Genetics: Redundancy ie. CD58 CD209 Janeway 7th Edn Fig8.17

  4. So what determines if there is Activation or Dissociation? All steps Ag non-specific. All common, transient, providing time for recog’n of specific Ag Stability comes from?

  5. T cell priming : 3 signals 1.Ag Activation 2. Costimulation 3. Cytokines! Homework: Choices and Consequences Self Ag/MHC alone? Foreign Ag alone? Costimulation alone? Ag plus costimulation?

  6. Different routes to costimulation Constitutive Functional differences exist/understanding “why” weak. “Directing Th1/Th2 commitment” > unlikely CD86 constitutive/upreg at 24h, CD80 “neg”, upreg at 48-72. Functional evidence for their importance Changing view of costimulation: The T:APC dialogue CD80/86

  7. APC T cell CD80, CD86 (B7 : B7.1 and B7.2 ) binds CD28 on T cell (restricted to lymphoid tissues, primarily “activn of naïve /memory T”) B7-H2 (LICOS), ICOS B7-H3 ??? (both seen widely expressed on non-lymphoid tissues, ie epithelium, primarily interacting with effectors? Not affected by CTLA4) B7 H3 selectively downregulates Th1 activity, favoring Th2: 2003 OX40 CD4 OX40L 4-1BB CD8 4-1BBL (mount normal CD4 or CD8 primary responses, but poorer secondary responses.) Many new co-stimulatory pathways by 2012 Costimulation-many pathways

  8. How do we control costimulation? 1. Regulating expression of costimulation partners 2. Introducing competitors – “negative signallers” :CTLA-4 (CD152) Normally absent, inducible, tightly regulated. • Ka 600-2500 higher for CD80/86 than CD28 • Intracellular protein stores: Ambiguous. Memory>>Naïve; Memory longer expn. • Constitutive on Treg • Soluble CTLA4 in plasma. Function? • CTLA4 deficient mice: activated T cell phenotype (CD69,25,44) among CD4 and CD8 T, spontaneous prolifn, Th1/Th2 cytokine prodn. • Therapeutic potential?

  9. CTLA4 -- the essential off signal • CTLA4, expressed by T cells upon activation, competes with CD80 or 86 for CD28. • Relevance to immune regulation • -/-: T cell hyperproliferation, cancer,death • elevated CTLA4: induction of tolerance?

  10. Survivor Immunology Now on CBS Watch them battle for the Prize????

  11. Using costimulation to modulate immune responses clinically Develop an experimental strategy to use costimulation to modulate developing or recall immune responses Controls, Readouts to test validity of your approach? Applications? Abatacept. Phase II trials for RA; Anti-CTLA4 mAb for tumor therapy >> ongoing Common theme: modulate existing undesirable host regulation of CTLA4.

  12. TcR expression is dynamic: Dr E. Palmer Key points: Low TcR during thymic development Activn results in drop then elevated expression of TcR on effector T cells Naïve SIMILAR TO memory

  13. Scenario 1 Why should Ag and costimulation need to be delivered by the same APC? (3 minutes) Scenario 2

  14. Your costimulation questions? Future 2-3 years • Costimulatory requirement of naïve vs memory? • CTLA4’s “natural role” and medical applications. • Relevance of other costimulatory molecules : tissue specific, spatially, or temporally localized expression, differential steering of intensity or quality of IR…) • Soluble molecules—junk or relevant? • Intracellular molecules - how to interpret?

  15. Annu Rev Immunol. 2010; Science paper cited at end of PPT Differentiation of Effector CD4 T Cell Populations. Zhu, Yamane, and WE Paul During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of Th cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function

  16. Annu Rev Immunol. 2010; Science paper cited at end of PPT Differentiation of Effector CD4 T Cell Populations. Zhu, Yamane, and WE Paul During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of Th cells, including Th1, Th2, Th17, and iTreg, as defined by their function and pattern of cytokine production Vote. Agree/Disagree/Concerned. Why?

  17. Th1/Th2 (review) basics... • Mosmann/Coffman ‘86: Murine CD4 T clones do not exhibit random patterns of cytokine gene expression following Ag stimulation Terminology • Th0: Ag-specific, activated CD4 T cell that has not yet committed to a Th1 or Th2 biased pattern of cytokine gene expression. • Th1: IFNg, TNF (not IL-2) • Th2: IL-4,IL-5,IL-13…(not IL-10) • Th3: TGFb, important in mucosal immunity, low dose tolerance (ie to food)… now largely called Treg • … Th17 , Th9, Th22 , ThU2 (Lord preserve us!)

  18. Th1/Th2 essentials: Key developments • Mid-late 1990’s : Many other cells in addition to CD4Th cells (ie CD8, mast, NKT…) exhibit Th1 or Th2-like cytokine production: Hence “Type 1 vs Type 2 biased” immunity. (not black/white at cell level or population) • Focus on : transcription factors as controllers of T cell fate (and biomarkers) • Concerns with lineage vs function > Plasticity. Th1/Th2 clones “can’t convert” (Ken Murphy …) • Are there more T cell lineages? Oh yeah… • However, way back… Th1 and Th2 subsets: paradigms lost?Anne Kelso 1995 Immunology Today (TIM)–a must read for your critical thinking.

  19. Appeal of the Type 1 / Type 2 (Th17,22,etc) hypothesis: Explains a widely observed correlation between:Differential production of specific cytokines (objectively quantified) Dominance of particular effector responses (murine IgE vs IgG2a) Clinical outcomes (acute vs chronic disease, allergic disease vs clinical tolerance)

  20. Suggests a ready avenue by which to direct de novo, and possibly pre-established, immune responses (Immunization programs, autoimmune disease, immediate hypersensitivity) Appeal of the Type 1 / Type 2 hypothesis:

  21. More Th cell types identified since 1986 …

  22. Semin Immunopathol. 2010 ; Ann Review Imm 2008 Follicular helper T cells T(FH) Recently emerged as a separate CD4 T helper lineage specialized in provision of help to B cells. Develop independently from Th1, Th2 and Th17 cells via a stepwise differentiation programme They are critical for humoral immunity, including the generation of long-lived and high affinity plasma cells and memory cells crucial for long-term protection against infections. Distinguishable from Th1 and Th2 cells by several criteria, including chemokine receptor expression (CXCR5), location (B cell follicles), and function (B cell help). Central to TFH function is IL-21, a "helper" cytokine that potently stimulates B differentiation into Ab-forming cells

  23. Despite an improved understanding of the molecular program that drives Tfh cell formation, their definition remains elusive: neither follicular homing ability, Bcl-6 expression nor IL-21 secretion are exclusive properties of T cells that help B cells, and not all follicular T cells are B cell helpers. Emerging cellular networks for TFH cells King C, Sprent J. Trends Immunol. 2012 Feb;33(2):59-65

  24. Th9 and allergic disease.T cell subset regulation in atopy Jutel M, Akdis CA. • Curr Allergy Asthma Rep. 2011 11:139-45. • TGFb 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008 • Murine Th2 cultured acutely with TGFb+IL4 > lose most Th2 cytokine capacity except IL9, acquire producing IL-10 capacity - Under certain conditions relevant to chronic disease (IL-4 and TGFb), a distinct population of IL-9-producing 'Th9' helper T cells can exist. - TGF-b constitutes a regulatory 'switch' that in combination with other cytokines (IL-4) can 'reprogram' effector T cell differentiation along different pathways PLoS One. 2010 Jan 14;5(1):e8706. Human CD4 memory T cells can become CD4+IL-9+ T cells.

  25. Th17 cell cytokine secretion profile in host defense and autoimmunity. Graeber KE, Olsen NJ. Inflamm Res. 2012 Feb;61(2):87-96 Recently defined CD4 T cell subset Initially appreciated from work on the role of IL-23 on EAE and CIA (2003, 2005) >> diseases previously blamed on excessive Th1 activity Produce IL-17A, IL-17F, IL-21, IL-22 Differentiation: TGFb, IL-6 Amplification: IL-21 Stability: IL-23 STAT3 is required for development and RORgammaT, a transcription factor is expressed by Th17 and required for Th17 development (common biomarker of Th17)

  26. Beneficial functions of Th17 in infection • Mobilize acute inflammation/neutrophilic responses (elicits secretion of attractant chemokines and matrix proteins to yield neutrophil recruitment) • Promote integrity of epithelial surfaces (inducing growth, differentiation and junctional integrity) • Protection against extracellular prokaryotes (Klebsiella and Citrobacter), Gram-negative bacteria and fungal infections, especially at epithelial surfaces

  27. Th17 in autoimmunity • IL-17 detected in target tissue of various human autoimmune diseases: multiple sclerosis, rheumatoid arthritis, psoriaisis • IL-17 deficient mice and IL-17R blocked mice are resistant to adjuvant-induced arthritis • IL-17 deficient mice show later onset and less severity of EAE (experimental autoimmune encephalomyelitis • Transfer of myelin-specific Th17 cell induce EAE in SJL mice • Many autoimmune diseases originally attributed to Th1 (IFNg) are now thought to be related to Th17

  28. Th22 IL-22 is a product of Th17 cells (and others). Role: mainly acts on epithelial cells and hepatocytes (not immune cells), where it favors antimicrobial defense, regeneration, and protection against damage and induces acute phase reactants and some chemokines “Differentation of skin homing IL22 producing T cells (Th22) can be promoted by acute exposure of naïve T cells in presence of IL-6 +TNF. Th22 is an inflammatory cell that is IL-22+, IL17-,IFNg- Important in inflammatory skin diseases (ie AD, psoriasis)

  29. Essentials • Cytokine production often associates clearly with particular effector responses (ie IL-4, IgE, clinical allergy): Response skewed towards Type 1 vs Type 2… bias in a broad spectrum of T cell activation • Type 1 immunity inhibits Type 2 (ie IFNg inhibits expression of IL-4, IL-13, Th2 associated chemokines, IgE synthesis…) and type 2 inhibits type 1 (ie inhibits proinflamm cytokines such as IFNg, shifts Ab bias…):Self regulating “balance of power” • Multiple patterns of “restricted T cell cytokine (and function)” expression apparent . Broadly similar in humans/mice …but not always in details

  30. New Topic: What drives Th1 vs Th2 vs ThXX differentiation? • Many factors drive commitment of naïve T cells towards Th1-like or Th2 like activation patterns. Such as... • Most important: Cytokines present at time of T cell priming • HOW? Acting on transcription factor expression. T-bet vs GATA-3 vs FoxP3 vs RORgT. • Key concept: Transcription factors as “markers” of T cell “commitment” (or current activity)

  31. Transcription factors as master regulators of T cell activation Naïve T cells (Th0) are negative for both Transcription Factors What induces T-bet vs GATA-3? IFNg STAT-1/IL-12 STAT-4 both drive T-bet IL-4/STAT-6 drives GATA-3 Both open up chromatin of approp genes Is memory plastic?

  32. Figure 1. Epigenetic modifications accompany progressive T helper cell differentiation Locksley Journal of Experimental Medicine 2009:206:1643-1646 IS plasticity of terminal effectors (Th1,2,9,17,22…) minimal? © 2009 Locksley

  33. Problems with this model of T cell regulation • Implies permanent commitment to one choice or the other. • T vs B analogy/Th1 vs Th2 analogy • Experimental contsraints (recognized/ignored?) Fresh vs cloned cells; add’n of cytokines in vitro • Is this a lineage commitment or a (transient) activation state? ie > Is commitment “permanent” or is it “plastic”? • Th17, Th9,Th22 –You too can discover a new cell lineage! • Watch models used, and conclusions drawn, carefully as results obtained frequently “model system specific”. • (ie not able to be broadly extrapolated)

  34. So, what do you do with all this? • What do you want to know? How will you use the info? • - Translational impact of a given immune response? • - Immune phenotype? • -T cell signaling? GLOBAL view: Type 1/Type 2 biased responses . Exam hint 

  35. Regulatory T cells Clonal deletion of autoreactive T cells in the thymus and Induction of T cell anergy in the periphery are the major mechanisms responsible for T cell tolerance BUT > the ability to detect autoreactive T cells in the periphery of healthy subjects indicates that: • neither of these is foolproof and • “additional mechanisms of immune tolerance must exist”. E. Shevach J. Exp. Med. July 2002 T:B collaboration H Claman 1969. Ts 1973 R. Gershon…today… Treg

  36. Regulatory cells and their ancestors… If God did not exist, it would be necessary to invent him. • Voltaire French author, humanist, rationalist, & satirist (1694 - 1778) How you ask the question, can determine the result you get. • Anonymous. Does expression of an activity reflect a transient activity or a permanent commitment (differentiation): T vs B cells, Th1/Th2, T reg, DC1/DC2…

  37. Regulatory T cells basics • Initial consensus definition of Treg: CirculatingT cells that act to inhibit autoreactive T cells by direct (cell/cell) interaction with them. • Expanded to regulating pathogen (L.major) , human allergy…responses. • Functionally defined as “suppressor cells” maintaining tolerance to self and… in some cases… foreign Ags. • Currently expanded operational definition: • CD4+CD25+ regulatory T cells (Tregs) control immune responses to self- and foreign antigens and play a pivotal role in autoimmune diseases, infectious and noninfectious inflammation, and graft rejection.

  38. The nature of regulatory T cells involved and the mechanism of suppression depend on the strength and stage of the pathological process.

  39. Regulatory T cells: how do they work? • Three major types initially identified: • Powrie CD4 CD25. Inhibit autoreactive T cells via IL-10 • Shevach CD4 CD25 inhibit autoreactive T cells via cell:cell contact. Not IL-10,IL-4 or TGFb dependent • Mason CD4 CD25, act via TGFb production. • Initial work predominately mouse, many recent studies in humans • Control of development, regulation of this lineage unclear. • Mechanism(s) by which they act unclear. Multiple lineages?

  40. Tregs • Require TcR mediated triggering but proliferate poorly. • Inhibit proliferation and (in fewer studies) cytokine production by effector (both CD4+,CD25- and CD8+) T cells. • Mechanisms of action both diverse and controversial. 15 distinct types as of 2010 citation • Initial evidence: IL-10 -/- mice exhibit lethal IBD as a result of uncontrolled production of inflammatory cytokines stimulated by normally trivial environmental (microbial) Ags. • Later: Foxp3 -/- transcription factor mice exhibit lymphoproliferative syndrome Congenital deficiency of CD4(+)CD25(+) Treg cells caused by loss-of-function mutations in the gene encoding Foxp3 triggers a syndrome of lymphoproliferation and myeloproliferation, autoimmunity, and allergic dysregulation. Minimum conclusion: These molecules are important components in normal immune regulation to self and foreign antigens

  41. Regulatory T cells (2012) • Natural Treg: (nTreg) CD4CD25FoxP3, in thymus, cell contact for suppression, self antigen focussed • Inducible/adaptive Treg, (iTreg) non-self antigen • Tr1: IL-10 • Th3: TGFb • 15 varieties … • Foxp3 expression prevents deviation of Treg cells into effector T cell lineages and confers dependence of Treg cell survival and expansion on growth factors, foremost interleukin-2, provided by activated effector T cells

  42. Regulatory T cells: Experimental Caveats • All activated T cells exhibit increased CD25 (high Ka IL2R a chain) upon activn, just as they do TcR • Treg are CD4,CD25+ but make up only 5-10% of this population. All assays to date based on functional properties--no way to obtain pure Treg as yet (no clear, commonly agreed phenotype). • Endogenous production of anti-inflammatory cytokines (IL-10,TGFb) by many cell types plays a key role in preventing chronic inflammation to self or to external stimuli. • Is this a separate lineage -- of committed, defined cell type(s)-- or is it an activity that might be expressed by multiple cell types in different circumstances? • Same difficulties as Th1 vs Th2, Th9,Th22…-biased immunity.

  43. Microorganisms can promote the induction of regulatory T cells to secure their own survival in their host. • Microorganisms can manipulate antigen-presenting cells (APCs) by interfering with co-stimulatory molecule expression, by modulating antigen presentation or by favouring the induction of regulatory cytokine production. • Some pathogens may have evolved such that their antigens now crossreact with self antigens and thereby can stimulate natural regulatory T (TReg) cells. • Tissue damage induced by pathological process may contribute to increased regulatory T-cell activity at sites of infection by favouring self-antigen presentation or by inducing cytokines that promote regulatory T-cell survival or induction.

  44. Diversification of CD4 T Cell Lineages (Immunity, Volume 24, P677-688, 2006)

  45. Heterogeneity and plasticity of T helper cells. Cell Res. 2010 Jan;20(1):4-12. Paul-WE

  46. Was Is O’Shea & Paul Science 2010

  47. Conclusions • A requirement for costimulation in Ag driven responses is absolute. This provides a major peripheral mechanism to prevent autoreactive T cells from being activated. (along with…?) • Different costimulatory pathways control (i) the intensity of adaptive immune activation (by controlling T cell activation) and (ii) the duration, diversity, affinity … of activation. • Th1/Th2, Thxxx and Treg provide models that can be used to pose questions about how the immune system is regulated but do not themselves provide a simple explanation for control • Their application to clinical or applied situations shows promise but can be limited by overly rigorous focus on the experimental model used:vaccines, allergy … Key in determining progress in this area will be differentiating discrete lineages from activation states • A wide variety of environmental factors can modulate immune capacity. Differentiating cause/effect from correlation for any given “immune modifier” (cytokine, cell subset, costimulatory molecule) will be challenging—and require critical thought rather than going with the herd.

  48. Minimum reading for exam • General overview: JanewayImmunobiologyChapter 8 relevant sections orAbbas (Cellular and Molecular Imm 6thEdn) T subsets : • The role of T helper subsets in autoimmunity and allergy. CurrOpinImmunol. 2009 Dec;21(6):606-11.Veldhoen-M Th cell subsets/plasticity, best update for 2012: Mechanisms underlying lineage commitment and plasticity in helper CD4 T cells O'Shea JJ, Paul WE. Science. 2010 327:1098 Treg • Plasticity of CD4(+) FoxP3(+) T cells.CurrOpinImmunol. 2009 Jun; 21:281 Bluestone-J • Plasticity of Foxp3 T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprograming of regulatory T cells. Miyao T, et al. Immunity. 2012 Feb (in press)

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