IMMUNOLOGICAL MEMORY. May 28, 2017

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1 IMMUNOLOGICAL MEMORY May 28, 2017 Francesca Di Rosa Institute of Molecular Biology and Pathology National Research Council

2 Pathogen infection and adaptive immune response

3 Primary T cell response (T cell numbers)

4 Secondary T cell response (T cell numbers) Harty JT and Badovinac VP Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol. (2008) 8:

5 Antibody primary and secondary response (Ab titer)

6 Secondary response gives protective immunity

7 Secondary response gives protective immunity Infection Re-Infection Innate Immunity (minutes, hours) Adaptive Immunity (days) Specific Immune Memory (months, years) Disease / Recovery No disease Adapted from Quaglino E, Cavallo F, Forni G, Le difese immunitarie (Piccin, 2010)

8 What is immunological memory? - a change in the immune system after its first encounter with the antigen How do we measure it? - by comparing the secondary response to the primary response (protection from infection, kinetics, antibody titer, class of Ab, frequency of antigen-specific T cells, ability to get a prompt effector T cell response, )

9 At the end of primary response.memory T CELLS Effector Naive Memory

10 Memory T cells as compared to naïve and effector T cells Characteris3cs Naïve T cells Effector T cells Memory T cells Persistence Months to years Hours to days Years to life5me Effector func5on Requires s5mula5on with Ag Immediate upon Ag recogni5on Requires res5mula5on with Ag but is faster and larger in magnitude than that of naïve T cells Migra5on Secondary lymphoid 5ssues Nonlymphoid 5ssues Both lymphoid and nonlymphoid 5ssues Adapted from Lakkis FG and Sayegh MH, Memory T cells: a hurdle to immunologic tolerance. (2003), J Am Soc Nephrol, 14,

11 Memory T cells Effector response upon rechallenge (Function / Quality) Number (Quantity) Phenotype (Surrogate for Quality) Development (Origin) Recirculation (Space)

12 Heterogeneity of effector T cell responses McKinstry KK et al. The potential of CD4 T-cell memory.immunology (2010) 130: 1-9.

13 Memory CD4 T cells in secondary response MacLeod MK, Clambey ET, Kappler JW, Marrack P. CD4 memory T cells: what are they and what can they do? Semin Immunol. (2009) 21:53-61.

14 Memory CD8 T cells in secondary response CMV, cytomegalovirus; LTNP, long-term non-progressor 5 functions = interleukin-2, interferon-gamma, tumour-necrosis factor, CC-chemokine ligand 4 and CD107 (cytotoxic degranulation) Seder RA et al. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol (2008) 8:

15 Memory CD8 T cells exhibit enhanced killing capacity NAIVE MOUSE MICE TRANSFERRED WITH MEMORY T CELLS Mixture of 2 types of CFSE-labelled target cells: CFSE high - unpulsed CFSE low pulsed with antigenic peptide Jabbari A, Harty JT Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype (2006) 203:

16 Decline of immune response and regulation of T cell numbers (homeostasis)

17 T cell numbers and protective memory Nature Reviews Immunology 2, (2002) Susan M. Kaech, E. John Wherry & Rafi Ahmed

18 More inflammation during primary response (IFN-γ, IL-12, IFN-I) => more CD8 T cells at peak expansion Harty JT and Badovinac VP Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol. (2008) 8:

19 More inflammation during primary response (IFN-γ) => less memory CD8 T cells Harty JT and Badovinac VP Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol. (2008) 8:

20 Inflammation and memory CD8 T cells Butler NS et al. Immunologic considerations for generating memory CD8 T cells through vaccination. Cell Microbiol (2011) 13:

21 Initial priming with CD4 T cell help is important for CD8 T cell numbers in secondary response Bevan MJ. Helping the CD8(+) T-cell response. Nat Rev Immunol (2004) 4:

22 Phenotype of naïve and memory T cells

23 Heterogeneity of memory T cells: Central and effector memory T cells CCR7= chemokine receptor for migration to lymph nodes

24 Heterogeneity of effector T cells: Short-Lived Effector Cells (SLECs) Memory Precursor Effector Cells (MPECs) KLRG1= killer cell lectin-like receptor subfamily G member 1 IL7Rα= α chain of IL-7 receptor (CD127) IL2Rα= α chain of IL-2 receptor (CD25) Lazarevic V et al. T-bet: a bridge between innate and adaptive immunity. (2013) 13:777-89

25 Memory T cell differentiation Linear model Divergent model Effector Memory Antigenactivated Antigenactivated Effector Memory Naive Antigenactivated Effector Memory time

26 Memory B cell and plasma cell differentiation Crotty S and Ahmed R. Immunological memory in humans Semin Immunol (2004) 16:

27 Asymmetric division in memory T cell differentiation?

28 Effector and memory T cell subset development? Lazarevic V et al. T-bet: a bridge between innate and adaptive immunity. (2013) 13:777-89

29 Progressive changes in T cell differentiation in adoptive transfers Restifo NP et al. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol (2012) 12:

30 Effector T cells migrate to the infection site to perform their function naive effectors Peripheral lymphoid organ Adapted from Gilboa E, The promise of cancer vaccines. (2004), Nat Rev Cancer, 4, Periphery (site of infection)

31 Different molecules regulate migration of naive and effector T cells

32 Example: skin-homing effector T cells

33 Protection of extra-lymphoid organs by effector memory T cells Adapted from Bevan MJ, Understand memory, design better vaccines. (2011), Nat Immunol, 12, 463-5

34 Immunological memory and lines of defense (classical view) Adapted from Bevan MJ, Understand memory, design better vaccines. (2011), Nat Immunol, 12, 463-5

35 Immunological memory and lines of defense (new view) Resident memory T cells Resident memory T cells (no exchange with circulation) Adapted from Bevan MJ, Understand memory, design better vaccines. (2011), Nat Immunol, 12, 463-5

36 Tissue-resident memory T cells control chronic infections EBV= Epstein-Barr Virus CMV = CytoMegaloVirus Woon HG, et al. (2016) Compartmentalization of Total and Virus-Specific Tissue-Resident Memory CD8+ T Cells in Human Lymphoid Organs. PLOS Pathogens 12(8): e

37 Bone marrow is a niche for memory T cells Tokoyoda K et al., Organization of immunological memory by bone marrow stroma. (2010), Nat Rev Immunol, 10, Di Rosa F and Pabst. R, The bone marrow: a nest for migratory memory T cells. (2005), Trends Immunol, 26, 360-6

38 Memory CD8 T cell entry and exit from the bone marrow bone marrow? stopping-over passing-through Recirculating Tissue-Resident in blood Migration Homeostatic Proliferation exit entry Di Rosa F Gebhardt T, Bone Marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells Frontiers Immunol (2016) 7:51

39 Memory T cells Effector response upon rechallenge (Function: heterogeneity, class of response, enhanced killing) Number (Quantity: frequency of antigen-specific T cells, regulation of numbers) Phenotype (Surrogate for Quality: activation/memory markers, definition of subsets based on marker expression) Development (Origin: linear/divergent models) Recirculation (Space: T RM, bone marrow as a niche for memory T cells)

40 Long-lived memory in humans Infec3on Dura3on of immunity (years) Measles on the Faroe Islands 65 Yellow fever virus in Norfolk, VA 75 Polio in remote Eskimo villages 40 Crotty S and Ahmed R. Immunological memory in humans Semin Immunol (2004) 16:

41 What is the immune system doing in between primary and secondary response? - nothing => memory T cells are long-lived memory cells have same life-span as naive, but higher frequency - something => memory T cells are stimulated through their TCR (persisting antigen, cross-reactive antigen, antibody idiotypes) not through their TCR (cytokines)

42 Slow proliferation of long-lived memory T cells Butler NS et al. Immunologic considerations for generating memory CD8 T cells through vaccination. Cell Microbiol (2011) 13:

43 Several cytokines influence T cell survival and proliferation Nature Reviews Immunology 2, (2002) Susan M. Kaech, E. John Wherry & Rafi Ahmed

44 IL-7 and IL-15 are master cytokines of memory T cells Schluns KS and Lefrancois L Cytokine control of memory T-cell development and survival Nat Rev Immunol (2003) 3:

45 Negative regulation by IL-2 dependent Treg cells Schluns KS and Lefrancois L Cytokine control of memory T-cell development and survival Nat Rev Immunol (2003) 3:

46 Antigen stimulation? persisting antigen; latent infection Antigen bound to FDC

47 Antigen stimulation? cross-reactive antigen Welsh RM and Selin LK. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol (2002) 2:

48 In normal life, infections come one after the other.

49 Heterologous protection LCMV = LymphoChorioMeningitis Virus VV = Vaccinia Virus Chen, HD et al. Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung. Nat Immunol (2001) 2:

50 Cross-reactivity and heterologous protection Welsh RM and Selin LK. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol (2002) 2:

51 Memory to antigen A is influenced by subsequent response to antigen B POSITIVE Antigen Cross-reactivity Or NEGATIVE Cytokine-mediated effect? Adapted from Schluns KS and Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol (2003) 3:

52 THE MOST IMPORTANT SUCCESS OF VACCINATION!!! SMALLPOX ERADICATION

53 Empirical observation (Edward Jenner) Observation: Individuals who have been exposed to vaccinia virus infection (cowpox) are protected against smallpox Hypothesis: Infection with cowpox gives immunity to smallpox. Testing the hypothesis: Successful vaccination in 1796!!!!

54 Vaccination is very effective against some infectious diseases

55 BUT. A better knowledge of immunological memory is really needed for new vaccine development.. Plasmodium falciparum (Malaria) Mycobacterium leprae (Leprosy) HIV (AIDS)

56 Some hope Seder RA et al. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol (200) 8: