First short refresh on tolerance

Transcription

1 First short refresh on tolerance

2 Death by neglect

3

4 What is the diversity of the T cell repertoire? Parham cites estimate from Arstila [Science, 1999]: 2x10 6 Nowadays next generation sequencing (NGS): Distinct TCRB sequences 2x10 8 1x10 8 5x10 7 2x10 7 1x10 7 CD4 naive T cells p= Age CD8 naive T cells p= Age Qi et al. PNAS 2014 Note that this is β-chains only! In mice almost every naive T cell unique TCR

5 Su et al. Immunity 2013 Number of Ag specific cells A Tet + cells (per 10 6 CD4) 100 No evidence for clonal deletion? Antigen Specificity: HIV CMV HSV-naive HSV-exposed FLU-HA FLU-PB1 FLU-PA tetanus Fib gp100 PPins Frequencies of tetramer-tagged cells per million CD4 T cells. Each symbol represents an antigen-specific population from one individual. Fib (fibrogen), gp100, PPins (preproinsulin): self antigens.

6 Michel Oldstone papers Ohashi et al Cell 1991, Oldstone et al Cell 1991: Induction of diabetes by viral infection of transgenic mice expressing LCMV protein in pancreas o mice are normal, no evidence for tolerance o infect mice with LCMV: virus is rejected but later mice develop diabetes

7 Polly Matzinger papers Anderson et al J Immunol 2001: Graft male tissue onto female mouse lacking an immune system o graft is rejected when immune system reconstitutes o graft is accepted when female receives a male thymus how to interpret this?

8 Testing Time-, Ignorance-, and Danger-Based Models of Tolerance Colin C. Anderson, 1 * Joseph M. Carroll, Stefania Gallucci,* John P. Ridge,* Allen W. Cheever, and Polly Matzinger* In this study, we present data showing that tolerance to Ags in the periphery is not determined by the time at which the Ag appears, or by special properties of tissues in newborn mice or newly developing immune systems. We placed male grafts onto immunoincompetent female mice, allowed the grafts to heal for up to 5 mo, and then repopulated the recipients with fetal liver stem cells. We found that the newly arising T cells were neither tolerant nor ignorant of the grafts, but promptly rejected them, though they did not reject female grafts, nor show any signs of autoimmunity. We also found that the H-Y Ag was continuously cross-presented on host APCs, that this presentation was immunogenic, not tolerogenic, and that it depended on the continuous presence of the graft. In searching for the stimulus that might activate the host APCs, we analyzed mrna expression with a highly sensitive real-time quantitative PCR assay. By using two different housekeeping molecules for comparison, we analyzed the message levels for several stress and/or inflammatory molecules in the healed grafts. We found that the long-healed grafts were not equivalent to normal skin because the healed grafts expressed lower levels of GAPDH. Altogether, these data suggest that acceptance vs rejection of peripheral tissues is not attributable to ignorance, timing-based tolerance, or special circulation properties of naive T cells in neonatal tissues. It is more likely attributable to an aspect of the context of Ag presentation that remains to be identified. The Journal of Immunology, 2001, 166: ARTICLES 2001 Nature Publishing Group Immunity or tolerance: Opposite outcomes of microchimerism from skin grafts COLIN C. ANDERSON & POLLY MATZINGER Ghost Lab, Section on T-cell Tolerance and Memory, Laboratory of Cellular and Molecular Immunology, NIAID/NIH Building 4 Room 111, 9000 Rockville Pike, Bethesda, Maryland , USA Correspondence should be addressed to C.C.A.; canderson@niaid.nih.gov

9 Testing Time-, Ignorance-, and Danger-Based Models of Tolerance FIGURE 1. Well-healed skin grafts induce immunity. A, B6 nude female mice (n 6) were given a B6 nude male skin graft and 9 wk later were given a neonatal B6 female thymus graft. B, B6 nude female recipients received a B10-RAG male skin graft and, 9 wk later, a neonatal male (dashed line; n 4) or female (solid line; n 4) B10-RAG thymus. C, B10-RAG female recipients (n 4) received two skin grafts, a B10-RAG female (dashed line) and male skin graft (solid line). Eleven weeks later, they were reconstituted with day-15 B6 female fetal liver cells. D, Thymectomized B10-RAG female recipients received a B10-RAG male skin graft and 7 wk later were reconstituted with day-15 B6 female fetal liver cells and thymus graft (solid line; n 6). Controls (dashed line) were similarly treated except they received a male fetal thymus graft (n 1) or a female skin graft (n 2).

10 A simple mathematical model

11 A simple mathematical model S number of self epitopes evoking tolerance (10 5 ) [Burroughs.i04] R0 potential repertoire (before tolerance) (huge: cells) R functional repertoire after tolerance (> 10 8 ) [Qi.pnas14] p recognition probability (precursor freq ) [Blattman.jem02] Size of functional repertoire: R = R 0 (1 p) S Probability of responding to foreign epitope: P i =1 (1 p) R Taking the derivative of Pi to p gives the optimum p = 1 S 10 5 De Boer & Perelson Proc Royal Soc 1993

12 A simple mathematical model Pi 1 Too specific Too much deletion 0.8 1/S SPECIFIC DEGENERATE Cross-reactivity (log(p))

13 Lymphocytes are specific AND recognize many peptides peptides 5 > 10 peptides Repertoire: 8 10 clones Because there are many more peptides ( ) than clones, we need sufficient cross-reactivity [Mason Imm. Today 98]. But each peptide is recognized by very few clones: p 10 5

14 none of the clonotypes recognizing foreign epitope or te we f = define 1 the a new newparameter l to induce tolerance. Incomplete model should f for the Otherwise tolerance be fraction identical of self to the epitop he new model should be identical the the clone previous will beone. heldfor a zed, l. [4] but we that let none be the of fraction the clonotypes of clonotypes recognizing recognizing the foreign is recognized, but that none of the clonotypes recog f S number of self epitopes evoking tolerance (0 < f <= 1) R0 potential repertoire, R functional repertoire, p precursor freq. )S self epitopes that fail to induce tolerance. Other itopes that fail to induce tolerance. Otherwise the clone will Borghans Following p) (1 f)s et. Borghans al. [4] we let et al. be[4] thewe fraction let of clonotypes (4) rec Fraction of clones recognizing at least one ignored self epitope: e, i.e., mulated with a foreign =1 (1 p) (1 f)s epitope is the probability that =1 (1 p) =1 (1 f)s.(1 p) spond (with chance p) and is potentially (1 f)s. auto-reactive rant Size when of functional stimulated repertoire: with a foreign epitope is the probabi Probability to remain tolerant: etoire R R= will R 0 (1respond p) fs (with. chance p) and is potentially (5) auto- the p ) probability R where that R = Rthe system remains tolerant and 0 (1 p) fs. emain P tolerant minus the chance to not respond at all: t = (1 p ) R where R = R 0 (1 p) fs. response is the probability that the system remains toler (1 he chance p) R, to remain tolerant minus the chance to not (6) respond Probability of a successful immune response: be the fraction mains tolerant when stimulated with a foreign epito ional repertoire R will respond (with chance p) and ul immune response is the probability that the sys, which is the chance to remain tolerant minus the cha o study P s = how P t incomplete (1 p) R, tolerance a ects the results we Borghans et al JI 1999

15 Regulatory T cells A T cell scans a DC The DC activates a T N cell p N = y N (1 - (1 - p) n ) The DC activates a T S cell A T R cell deactivates the DC p S = y S (1 - (1 - p) n + m (1- f ) ) p R = y R (1 - (1 - p) n + m (1- f (1 - α)) ) No interaction p U = 1- p N - p S - p R Saeki et al JTB 2015

16 MHC: very polymorphic but not diverse. Hundreds of alleles in every population Almost everyone heterozygous at every locus 6 major loci: 12 different MHC molecules per host Why not many more?

17 MHC diversity within an individual p probability of positive selection n probability of negative selection Note p > n M number of MHC molecules per host Clones should not be negatively selected on any MHC but should be positively selected by at least one MHC: R = R 0 (1 n) M (1 p) M In mice about 3% of the thymocytes survive and about half of the positively selected cells become negatively selected [Van Meerwijk et al., Merkenschlager et al., J Exp Med 1997]

18 R = R 0 (1 n) M (1 p) M 0.3 R/R MHC diversity (log M) 3 4 Parameters p=0.01 and n=p/2=0.005 [Borghans Eur J Imm 2003]

19 A simulation model: Borghans, Int. Immunol bacterial peptides viral peptides... toxin peptides self peptides Repertoire Set of peptides for each antigen group. Clones will recognize peptides from all sets with probability p.

20 Play an immune system game 1. Make a pathogen by drawing e epitopes from its set 2. Determine phenotype of all clones responding 3. If all naive: switch them to memory of corresponding mode 4. If memory available: switch all to that mode determine succes 5. Goto 1.

21 A simple example Clone numbers: Ro Initial types: Antigen 1, type 7: Zero score Antigen 2, type 5: Zero score Antigen 3, type 5: Positive score Antigen 4, type 9: Negative score

22 10e3 epitopes per set, 10e6 clones Fraction immune responses response positive negative autoimmunity Lymphocyte cross reactivity (p)

23 Fig. 3. The performance of a diverse immune system. The fractions of different immune responses have been plotted for different degrees of cross-reactivity (p), after challenge with 10 3 different pathogens. The thick curve denotes the fraction of challenges that induce any immune response at all. The fraction of challenges in which pre-existing effector/memory clones induce the correct type of immune response is denoted by the thin curve. The fraction of challenges in which pre-existing effector/memory clones induce an inappropriate immune response is denoted by the dashed curve. The fraction of challenges leading to autoimmunity, caused by ignorant self-speci c clones that are triggered by foreign antigens, is denoted by the dash-dotted curve. This repertoire is most functional at a cross-reactivity of p ~ 10 ±6, because the chance of immunity is then close to 1, and the net contribution of pre-existing effector/memory cells is high. There are e = 6 different epitopes per pathogen, pathogens come from m ± 1 = 8 different groups, each consisting of N = 10 3 different epitopes, a fraction f = 0.8 of all S = 10 4 self epitopes induces tolerance and there are R 0 = 10 6 clonotypes.