What determines the CD4:CD8 T cell ratio in the immune system?

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1 What determines the CD4:CD8 T cell ratio in the immune system? Insights from genetic and mathematical modelling of thymocyte development Benedict Seddon 1

2 Cell of the immune system 2

3 Maintaining homeostasis of the T cell compartment Thymus Periphery Double Negative CD4 + CD8 + Double Positive Single Positive Naive Effector Memory CD4 + Homeostatic cell division Homeostatic cell division +ve selection activation CD8 + Apoptosis Apoptosis Apoptosis 3

4 Maintaining homeostasis of the T cell compartment Thymus Periphery Double Negative CD4 + CD8 + Double Positive Single Positive Naive Effector Memory CD4 + Homeostatic cell division Homeostatic cell division +ve selection activation CD8 + Apoptosis Apoptosis Apoptosis 3

5 How and why does the thymus make more CD4 than CD8 cells?? 71% Andy Yates + + CD4 13% CD8 Characteristic 4:1 ratio - Conserved across species Why? 4

6 Thymocyte selection - two purposes 1. Tolerance - delete autoreactive T cells spmhc TCR Delete Kill thymocytes Select Useful self Neglect Kill thymocytes with with Autoreactive recognition uselesstcrs 5

7 Thymocyte selection - two purposes 2. CD4 vs CD8 lineage specification ensuring TCR-MHC restriction and lineage correlate TEC/DC Class II MHC "!# Class I MHC!2 microglobulin CD4 CD8 T cell receptor peptide Thymocyte! "# 6

8 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

9 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

10 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

11 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP 3 CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD5 TCR CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

12 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP 3 CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD5 TCR CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

13 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP 3 CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD5 TCR CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

14 Thymic development - what happens CD4 CD8 Double Negative CLP (Bone marrow) DN1 CD44 hi CD25 lo DN2 CD44 hi CD25 hi DN3 CD44 lo CD25 hi DN4 CD44 lo CD25 lo CD4 SP TCRβ rearrangement Medulla Cortex CD4 DN CD8 SP CD8 CD8 SP 3 CD4 SP 3 TCR hi CD5 int TCR int CD5 hi TCR lo CD5 lo CD5 TCR CD4 CD8 Double Positive Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 7

15 Thymic development - how it happens TCR T cells need signals from TCR to develop MHC T cell TEC or DC 8

16 Positive and negative selection - goldilox models frequency amongst repertoire neglect (>9%) selection (5%) delete (1-5%?) avidity TCR for spmhc 9

17 Lineage commitment - signals instruct fate Kinetic Quantitative instructive CD4! CD4! CD4 SP! Continuous" signals! CD4 hi CD8 lo! CD4 + CD8 + "! CD4 SP! " Strong TCR signals! CD4 + CD8 + "! IL-7r! + Intermittent! signals! +IL7! Weak" TCR" signals! DN! CD8 SP! DN! CD8 SP! CD8! CD8! 1

18 Origin of CD4 biased selection Thymus Double Negative CD4 + CD8 + Double Positive Single Positive CD4 + +ve selection CD Instrinsic differences in Class I and Class II restricted precursors due to TCR repertoire generation 2. Differences in efficiency of selection between CD4 and CD8 lineage cells 11

19 Zap7 deficient mice blocked at double positive stage MHC presenting peptide antigen WT Zap7 KO Co-receptors TCR CD3 complex CD CD8 p56 lck Role of Zap7 in positive selection : Zap7 Conditionally express Zap7 MAP Kinases, NFκB, Calcium signalling 12

20 Conditional Zap7 expression mouse model T cell specific expression of rtta fusion protein rtta hucd2 promotor - reverse tetracyclin TransActivator IRES TRE Zap7 hucd2 reporter SV4 PolyA splice Zap7 Tre rtta.c hucd2 Zap7 -/- Zap7 Tet mice 13

21 Conditional Zap7 expression mouse model T cell specific expression of rtta fusion protein Doxycycline (administered in vivo or in vitro) Zap7 protein rtta hucd2 promotor - reverse tetracyclin TransActivator IRES TRE Zap7 hucd2 reporter SV4 PolyA splice Zap7 Tre rtta.c hucd2 Zap7 -/- Zap7 Tet mice Zap7 -/- WT TetZap7 Zap7 13

22 Inducible T cell development dc TCR T cells need signals from TCR to develop MHC T cell Genetic mutant with inducible TCR signalling TreZap OFF 6-8wks TreZap ON + Dox food TetZap7 14

23 Inducible T cell development thymocytes : SP thymocytes : 15

24 Establishing precursor-product relationships CD4 CD5 Intra-thymic injection CD8 TCR Cell sort 96 3 CD5 TCR 3.9 d1-6 Measure relative recovery MoFlo X 16

25 Establishing precursor-product relationships - I 17

26 Establishing precursor-product relationships - II 3 18

27 Temporal dynamics of positive selection CD4 CD4 SPs CD8 gated : 24h 3 3 Non-selecting CD8 SPs 72h CD5 CD5 TCR TCR Saini, M. et al. Regulation of Zap7 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci Signal 3, ra23 (21). 19

28 Temporal regulation of thymic selection CD4 SP 3 CD4 CD8 SP CD5 CD8 TCR 3 CD4SP CD8SP Thymic output 2

29 Mathematical description of development CD4 SP 3 CD4 CD8 SP CD5 CD8 TCR δ1 δ2 δ3 λ (!1) (!2) µ12 µ23 3 (!3) Population dynamics dx 1 dt dx 2 dt = λ (δ 1 + µ 12 )x 1 [t] = µ 12 x 1 [t] (δ 2 + µ 23 + µ 24 )x 2 [t] µ24 µ38 dx 3 dt dy 4 dt = µ 23 x 2 [t] (δ 3 + µ 38 )x 3 [t] = µ 24 x 2 [t] ν 4 y 4 [t] CD4SP (!4) CD8SP (!8) dy 8 dt = µ 38 x 3 [t] ν 8 y 8 [t]!4!8 Thymic output 21

30 Generating timecourse data of Class I and Class II restricted T cell development Control Both lineages Control TetZap7 TreZap OFF 6-8wks TreZap ON Class II restricted CD4 lineage Class I KO Class I KO TetZap7 D, 1, 2, 3, Phenotype thymus δ1 δ2 δ3 Class I restricted CD8 lineage Class II KO Class II KO TetZap7 λ (!1) (!2) µ12 µ23 3 (!3) µ24 µ38 CD4SP ("4) CD8SP ("8) #4 #8 Thymic output 22

31 Control time course % total thymus CD4 SPs 2. CD8 SPs

32 Class I vs Class II resticted T cell development % total thymus Class II restricted Class I restricted Controls b2m KO Class II KO CD4 SPs CD8 SPs

33 Use data to identify parameters of model Log vs Lin transformed data Assume SP plateau Parameter estimations by minimising sum of squares residuals (Nelder-Mead algo in R) % total thymus CD8 SPs Controls b2m KO Class II KO Rag-control MHC I KO MHC II KO Rag control MHC I knockout MHC II knockout Parameter Estimate 95% CI Estimate 95% CI Estimate 95% CI λ (25.95, ) µ (.76,.16).8 (.55,.16).61 (.43,.8) µ (.234,.56).299 (.116,.482).48 (.196,.763) µ (.393,.575).583 (.473,.692).12 (-.19,.43) µ (-.697, 1.27).12 (-.27,.51).136 (-.153,.424) δ (.218,.281).251 (.214,.289).251 (.219,.283) δ (.441,.866).781 (.365, 1.197).792 (.427, 1.158) δ (-.884, 1.171).317 (-.34,.669).378 (-.392, 1.149) ν4.23 (.132,.327).142 (.58,.225) - - ν8 1 (-3.289, 5.289) (-.72,.92) Mean time spent in (days) 1 µ 12 +δ Mean time spent in 1 µ 23 +µ 24 +δ Mean time spent in 3 1 µ 38 +δ Mean time spent in CD4SP 1 ν Fraction of that die Fraction of recruited to Fraction of that die Fraction of recruited to 3 Fraction of recruited to CD4SP Fraction of 3 that die δ 1 µ 12 +δ µ12 µ 12 +δ δ 2 µ 23 +µ 24 +δ µ23 µ 23 +µ 24 +δ µ24 µ 23 +µ 24 +δ δ 3 µ 38 +δ µ38 Fraction of 3 recruited to CD8SP µ 38 +δ We assumed: (i) the rate of input into the compartment of cells (cells/day) (from DNs) was the same in the WT, MHC I KO and MHC II KO mice (ii) CD4 and CD8 cell numbers are at steady-state (or plateau) from day 7 onwards. We use this assumption to constrain our estimate for the rate of export from the SP compartments. All other parameters were completely free. The 95% CI come from a bootstrap procedure: I create a new dataset by randomly re-sampling the observations (with replacement) and find new set of parameters to describe this resampled-dataset. I repeat this n=1^4 times. The 2.5 and 97.5 percentiles of the new parameters is used to determine the 95% confidence intervals. 25

34 Model fits to timecourses of T cell development Class I + Class II restricted δ1 δ2 δ Obs Pred λ (!1) (!2) µ12 µ23 3 (!3) µ24 µ CD4 SPs CD8 SPs CD4SP ("4) CD8SP ("8) #4 #8 Thymic output Class II restricted Class I restricted Obs Pred CD4 SPs 2. CD8 SPs 8 CD4 SPs 2. CD8 SPs

35 Maturation rates in different hosts δ1 δ2 δ3 λ =.23 λ (!1) (!2) µ12 µ23 3 (!3) 4+8 = control - both CD4 and CD8 lineages 4s = CD4 lineage only (Class I KOs) 8s = CD8 lineage only (Class II KOs) CD4SP ("4) µ24 µ38 CD8SP ("8) Rate (/cells/day) #4 #8 Thymic output s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s to - CD4 SP -3 3 to CD8 SP (!12) (!24) (!23) (!38) µ12 µ24 µ23 µ28 27

36 Maturation rates in different hosts δ1 δ2 δ3 λ =.23 λ (!1) (!2) µ12 µ23 3 (!3) 4+8 = control - both CD4 and CD8 lineages 4s = CD4 lineage only (Class I KOs) 8s = CD8 lineage only (Class II KOs) CD4SP ("4) µ24 µ38 CD8SP ("8) Rate (/cells/day) #4 #8 Thymic output s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s to - CD4 SP -3 3 to CD8 SP (!12) (!24) (!23) (!38) µ12 µ24 µ23 µ28 27

37 Maturation rates in different hosts δ1 δ2 δ3 λ =.23 λ (!1) (!2) µ12 µ23 3 (!3) 4+8 = control - both CD4 and CD8 lineages 4s = CD4 lineage only (Class I KOs) 8s = CD8 lineage only (Class II KOs) CD4SP ("4) µ24 µ38 CD8SP ("8) Rate (/cells/day) #4 #8 Thymic output s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s to - CD4 SP -3 3 to CD8 SP (!12) (!24) (!23) (!38) µ12 µ24 µ23 µ28 27

38 Death during selection δ1 δ2 δ3 4+8 = control - both CD4 and CD8 lineages 4s = CD4 lineage only (Class I KOs) 8s = CD8 lineage only (Class II KOs) 1.5 λ (!1) (!2) µ12 µ23 CD4SP ("4) 3 (!3) µ24 µ38 CD8SP ("8) #4 #8 Rate (/cell/day) 1..5 Thymic output s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s (!1) (!2) 3 (!3) CD4 SP ( v4) CD8SP (v8) 28

39 Death during selection δ1 δ2 δ3 4+8 = control - both CD4 and CD8 lineages 4s = CD4 lineage only (Class I KOs) 8s = CD8 lineage only (Class II KOs) 1.5 λ (!1) (!2) µ12 µ23 CD4SP ("4) 3 (!3) µ24 µ38 CD8SP ("8) #4 #8 Rate (/cell/day) 1..5 Thymic output s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s (!1) (!2) 3 (!3) CD4 SP ( v4) CD8SP (v8) 28

40 Cellular fate during development Both (Control hosts) 75% 25% 71% 1% 19% 63% 37% CD4 SP 4.6% CD8 SP 1.5% CD4 lineage only (Class I KO) 81% 19% 46% 33% 21% 97% 3% CD4 SP 4.4% CD8 lineage only (Class II KO) 76% 24% 93% 7% 97% 3% CD8 SP 1.7% 29

41 Testing for high death rate in thymocytes CD4 CD5 Intra-thymic injection CD8 TCR Cell sort 96 3 CD5 3.9 d2 TCR + Zap7 -/- thymocytes + Zap7 -/- thymocytes + Zap7 -/- thymocytes Measure relative recovery MoFlo X 3

42 1.5 Death rates Rate (/cell/day) s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s 4+8 4s 8s (!1) (!2) 3 (!3) CD4 SP ( v4) CD8SP (v8) 1 In vivo survival Relative survival hucd2- hucd2+ WT WT WT 3 WT CD4 WT CD8 CyAn A 31

43 Distinct death rates amongst Class I and Class II restricted s Model Observed Rate (/cell/day) Relative survival * s 8s 4+8 4s 8s (!1) (!2) Death rate 8s =.88 Death rate 4s =.27 CD4 lin b2mko CII KO CD8 lin Survival 8s/survival 4s Relative survival : e -.88 /e -.27 = /3.14 =.55 32

44 Using lineage specific death rates to quantify lineage efficiencies 1.5 Rate (/cell/day) s 8s 4+8 4s 8s (!1) (!2) Both (Control hosts) 75% 25% 71% 1% 19% 63% 37% CD4 SP 4.6% CD8 SP 1.5% 33

45 Modeling reveals unexpectedly high CD8 lineage biased death in selection δ1 δ2 δ3 λ (!1) (!2) µ12 µ23 3 (!3) µ24 µ38 CD4SP ("4) CD8SP ("8) 14% CD8 36% 81% 19% #4 #8 75% 11% CD4 64% 55% 45% 3 Death CD4SP CD8SP 34

46 Regulation of thymocyte survival Derepressors Inhibitors Executioners Bad -ve Bcl2 Bax Bmf Noxa BclXl Mcl1 +ve Bak Activators Bid Bim Mitochondria Cytochrome C release APOPTOSIS 35

47 Paralogous switch between Bcl-2 and Bcl-Xl sensitises thymocytes to negative selection 15 Bcl2 2 BclXl 25 Mcl1 Inhibitors Expression (nrpkm) Bim (Bcl2l11) Activators Bid Bad Derepressors Bmf 5 Bax 5 Bak1 Executioners CD8 SP CD4 SP HSA hi CD4 SP HSA lo

48 Test the impact of apoptosis - introduce apoptotic stress to thymocytes 14% CD8 36% 81% 19% Executioners 75% 11% CD4 64% 55% 45% Bax Bak 5 Bax Mitochondria Bax hucd2 Transgenic mice Cytochrome C release APOPTOSIS 37

49 StBStB 2.jo2.jo Layout: Thy-Batch Layout: Thy-Batch Applying apoptotic stress preferentially kills CD8 lineage cells Single Positive HSAhi CD StBStB 2.jo2.jo Total 2.2 Live Cells Live Cells StB_T 2.fcs StB_T 2.fcs Count: Live Cells Live Cells StB_T StB_T 1.fcs 1.fcs StBStB 2.jo2.jo Layout: Thy-Batch Layout: Thy-Batch CD8+ Live Cells Live Cells Count: StBStB 2.jo2.jo Count: Total CD8 Live Cells Live Cells StB_T 3.fcs StB_T 3.fcs Count: Count: Naive T Live cells Cells Live Cells StB_LN 1.fcs 2.fcs StB_T StB_T 2.fcs Count: Count: StB lo 2.jo CD44 naive TCR StB_T 3.fcs StB_T 3.fcs Count: RTEs RTEs StB_LN 1.fcs StB_LN 1.fcs 2.fcs StB_T StB_T 2.fcs Count: Count: Count: Count: StB 2.jo RTE 66 HSAhi HSAhi StB_T 2.fcs StB_T 2.fcs Count: HSAhi HSAhi 2717 Count: StB 2.jo CD5 CD StB 2.jo StB_T 2.fcs StB_T 2.fcs Count: Count: CD4 Live Cells Live Cells StB_T 2.fcs StB_T 2.fcs Count: Live Cells Live Cells StB_T StB_T 1.fcs 1.fcs Live Cells Live Cells StB_T 3.fcs StB_T 3.fcs Count: TCount: Naive cells Cells Live Live Cells StB_LN 1.fcs 2.fcs StB_T StB_T 2.fcs Count: Count: CD44lo CD44lo Count: CD StB lo 2.jo Layout: Thy-Batch Layout: Thy-Batch HSAhi TCRhi HSAlo TCRhiCD44 naive WT Bax HSAhi HSAhi 2717 Count: CD44lo CD44lo StB_T 2.fcs StB_T 2.fcs Count: CD44lo CD44lo Count: CD8 HSAhi HSAhi StB_T 3.fcs StB_T 3.fcs 3389 Count: 3389 Count: Mature Mature HSAhi HSAhi StB_LN StB_LN1.fcs 1.fcs StB_T StB_T 2.fcs 2.fcs Count: Count: Count: 32 Bax 23 CD44lo CD44lo StB_T 3.fcs StB_T 3.fcs 4855 Count: 4855 CD44lo CD44lo StB_T StB_T 2.fcs 2.fcs Count: Mature naive Layout: LN-Batch-1.11 TCR StB_T 3.fcs StB_T 3.fcs Count: RTEs RTEsCount: StB_LN 1.fcs StB_LN 1.fcs 2.fcs StB_T StB_T 2.fcs Count: Count: Count: Count: StB 2.jo RTE 11 Qa2 Naive T cells Live Cells StB_LN 3.fcsCells Live Naive TCount: cells StB_T 4.fcs StB_T 4.fcs StB_LN 2.fcs Count: Layout: LN-Batch-1 44 Layout 71 HSAhi HSAhi StB_T 3.fcs StB_T 3.fcs 3389 Count: 3389 Count: Mature Mature HSAhi HSAhi StB_LN StB_LN1.fcs 1.fcs StB_T 2.fcs StB_T 2.fcs Count: Count: Count: Count: 23 CD44lo CD44lo StB_T 3.fcs StB_T 3.fcs 4855 Count: 4855 CD44lo CD44lo StB_T 2.fcs StB_T 2.fcs Count: Mature naive Layout: LN-Batch-1 34 HSAhi HSAhi StB_T 4.fcs StB_T 4.fcs Mature Mature 1884 Count: 1884 HSAhi StB_LN2.fcs 2.fcs HSAhi StB_LN StB_T 3.fcs StB_T 3.fcs Mature Count: Count: Mature Count: 3389 StB_LN1.fcs 1.fcs StB_LN Count: Count: Count: Count: /9/12 13:12 26/9/12 13:12 32 Layout W B Layout: LN-Batch CD44lo CD44lo StB_T 2.fcs StB_T 2.fcs Count: CD44lo CD44lo Count: StB_T 4.fcs StB_T 4.fcs RTEsCount: RTEs Count: StB_LN 2.fcs StB_LN 2.fcs StB_T 3.fcs StB_T fcs RTEs Count: Count: RTEs Count: Count: StB_LN 1.fcs64381 StB_LN 1.fcs CD8 83 Live Cells Live Cells StB_T 4.fcs StB_T 4.fcs Count: Naive cells TCount: Live Cells Live StB_LN 2.fcsCells StB_T 3.fcs StB_T 3.fcs Naive TCount: cells StB_LN 1.fcs Count: 66 HSAhi HSAhi StB_T 2.fcs StB_T 2.fcs Count: HSAhi HSAhi 2717 Count: StB 2.jo WT Layout: LN-Batch-1 44 StB_T 2.fcs StB_T 2.fcs Count: Count: CD5 Bax CD StB 2.jo Layout: Thy-Batch 51 Mature 1.4 naive Thymic Emigrants CD44lo CD44lo Count: Layout: Thy-Batch HSAhi TCRhi HSAlo TCRhi Recent HSAlo WT HSAhi HSAhi 2717 Count: 2717 Naive CD4 CD4+CD8+ Double Positive Count: Page Page 1 of11of CD8 RTEs RTEs StB_LN 3.fcs StB_LN 3.fcs RTEs Count: Count: 594 RTEs StB_T 4.fcs StB_T594 4.fcs StB_LN 2.fcs StB_LN 2.fcs Count: Count: Count: Count: CD4:CD8 ratio Live Cells Live Cells Count: HSA Double Negative Periphery CD4 Thymus 15 CD44lo CD44lo StB_T 4.fcs StB_T 4.fcs 2223 Count: 2223 CD44lo CD44lo StB_T 3.fcs StB_T 3.fcs 4855 Count: (FlowJo v9.4.1) (FlowJo v9.4.1) 15 Mature Mature StB_LN3.fcs 3.fcs HSAhi StB_LN HSAhi Mature Count: Count: 4174 Mature 4174 StB_T 4.fcs StB_T 4.fcs StB_LN2.fcs 2.fcs StB_LN 1884 Count: 1884 Count: Count: HSAhi RT CD44lo CD44lo StB_T 4.fcs StB_T 4.fcs 2223 Count: 2223 Layout: LN-Batch 38

50 CD4:CD8 ratio only affected by Bax during stage Thymus Periphery Double Negative CD4 + CD8 + Double Positive HSAhi CD4 + Single Positive HSAlo Recent Thymic Emigrants Naive Mature naive CD4:CD8 ratio WT Bax CD8 + HSAhi RTE Mature HSAhi RTE Mature 39

51 From the Lab Charles Sinclair Iren Bains Thanks to... New York Andy Yates, Albert Einstein College of Medicine, NY, US 4

52 TetZap7 development vs WT CD4 lineage CD8 lineage 3 3 >95%? WT CD4SP WT CD8SP ~2% 3 3 8% TetZaps CD4SP TetZaps CD8SP 41

53 Establishing precursor-product relationships CD4 CD5 Intra-thymic injection CD8 TCR Cell sort 96 3 CD5 TCR 3.9 d1-6 Measure relative recovery MoFlo X 42

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