Lower affinity T cells are critical components and active participants of the immune response

Frontiers in Immunology

Volumn 6, Issue SEP, 2015, Pages

  Martinez, Ryan J ^a   Evavold, Brian D ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

2D assays; T cell diversity; T cells; TCR affinity; Tetramers

Indexed keywords

INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; MYC PROTEIN; T LYMPHOCYTE RECEPTOR;

ANTIGEN DETECTION; ANTIGEN PRESENTING CELL; ANTIGEN SPECIFICITY; ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; HUMAN; IMMUNE RESPONSE; LYMPHOCYTE FUNCTION; MAJOR HISTOCOMPATIBILITY COMPLEX; NONHUMAN; PROTEIN BINDING; RECEPTOR AFFINITY; SIGNAL TRANSDUCTION; SURFACE PLASMON RESONANCE; T LYMPHOCYTE ACTIVATION; UPREGULATION;

EID: 84949567457     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2015.00468     Document Type: Article

References (119)

1. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol (2014) 14:377-91. doi: 10.1038/nri3667
2. Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol (2012) 4:a006957. doi:10.1101/cshperspect.a006957
3. Zhu C, Jiang N, Huang J, Zarnitsyna VI, Evavold BD. Insights from in situ analysis of TCR-pMHC recognition: response of an interaction network. Immunol Rev (2013) 251:49-64. doi:10.1111/imr.12016
4. Blanchfield JL, Shorter SK, Evavold BD. Monitoring the dynamics of T cell clonal diversity using recombinant peptide: MHC technology. Front Immunol (2013) 4:170. doi:10.3389/fimmu.2013.00170
5. Busch DH, Pamer EG. T cell affinity maturation by selective expansion during infection. J Exp Med (1999) 189:701-10. doi:10.1084/jem.189.4.701
6. Malherbe L, Hausl C, Teyton L, McHeyzer-Williams MG. Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity (2004) 21:669-79. doi:10.1016/j.immuni.2004.09.008
7. Zehn D, Lee SY, Bevan MJ. Complete but curtailed T-cell response to very low-affinity antigen. Nature (2009) 458:211-4. doi:10.1038/nature07657
8. Kersh AE, Edwards LJ, Evavold BD. Progression of relapsing-remitting demyelinating disease does not require increased TCR affinity or epitope spread. J Immunol (2014) 193:4429-38. doi:10.4049/jimmunol.1401456
9. Sabatino JJ, Huang J, Zhu C, Evavold BD. High prevalence of low affinity peptide-MHC II tetramer-negative effectors during polyclonal CD4+ T cell responses. J Exp Med (2011) 208:81-90. doi:10.1084/jem.20101574
10. Stone JD, Kranz DM. Role of T cell receptor affinity in the efficacy and specificity of adoptive T cell therapies. Front Immunol (2013) 4:244. doi:10.3389/fimmu.2013.00244
11. Kuo SC, Lauffenburger DA. Relationship between receptor/ligand binding affinity and adhesion strength. Biophys J (1993) 65:2191-200. doi:10.1016/S0006-3495(93)81277-3
12. Huang J, Zarnitsyna VI, Liu B, Edwards LJ, Jiang N, Evavold BD, et al. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature (2010) 464:932-6. doi:10.1038/nature08944
13. Huppa JB, Axmann M, Mörtelmaier MA, Lillemeier BF, Newell EW, Brameshuber M, et al. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature (2010) 463:963-7. doi:10.1038/nature08746
14. Chesla SE, Selvaraj P, Zhu C. Measuring two-dimensional receptor-ligand binding kinetics by micropipette. Biophys J (1998) 75:1553-72. doi:10.1016/S0006-3495(98)74074-3
15. Liu B, Zhong S, Malecek K, Johnson LA, Rosenberg SA, Zhu C, et al. 2D TCR-pMHC-CD8 kinetics determines T-cell responses in a self-antigen-specific TCR system. Eur J Immunol (2014) 44:239-50. doi:10.1002/eji.201343774
16. Adams JJ, Narayanan S, Liu B, Birnbaum ME, Kruse AC, Bowerman NA, et al. T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity (2011) 35:681-93. doi:10.1016/j.immuni.2011.09.013
17. Hamad AR, O'Herrin SM, Lebowitz MS, Srikrishnan A, Bieler J, Schneck J, et al. Potent T cell activation with dimeric peptide-major histocompatibility complex class II ligand: the role of CD4 coreceptor. J Exp Med (1998) 188:1633-40. doi:10.1084/jem.188.9.1633
18. Crawford F, Kozono H, White J, Marrack P, Kappler J. Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity (1998) 8:675-82. doi:10.1016/S1074-7613(00)80572-5
19. Stone JD, Artyomov MN, Chervin AS, Chakraborty AK, Eisen HN, Kranz DM. Interaction of streptavidin-based peptide-MHC oligomers (tetramers) with cell-surface TCRs. J Immunol (2011) 187:6281-90. doi:10.4049/jimmunol.1101734
20. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, et al. Phenotypic analysis of antigen-specific T lymphocytes. Science (1996) 274:94-6. doi:10.1126/science.274.5284.94
21. Kim C, Wilson T, Fischer KF, Williams MA. Sustained interactions between T cell receptors and antigens promote the differentiation of CD4+ memory T cells. Immunity (2013) 39:508-20. doi:10.1016/j.immuni.2013.08.033
22. Dougan SK, Dougan M, Kim J, Turner JA, Ogata S, Cho H-I, et al. Transnuclear TRP1-specific CD8 T cells with high or low affinity TCRs show equivalent anti-tumor activity. Cancer Immunol Res (2013) 1:99-111. doi:10.1158/2326-6066.CIR-13-0047
23. al-Ramadi BK, Jelonek MT, Boyd LF, Margulies DH, Bothwell AL. Lack of strict correlation of functional sensitization with the apparent affinity of MHC/peptide complexes for the TCR. J Immunol (1995) 155:662-73.
24. Zhong S, Malecek K, Johnson LA, Yu Z, Vega-Saenz de Miera E, Darvishian F, et al. T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proc Natl Acad Sci U S A (2013) 110:6973-8. doi:10.1073/pnas.1221609110
25. Derby MA, Wang J, Margulies DH, Berzofsky JA. Two intermediate-avidity cytotoxic T lymphocyte clones with a disparity between functional avidity and MHC tetramer staining. Int Immunol (2001) 13:817-24. doi:10.1093/intimm/13.6.817
26. Mandl JN, Monteiro JP, Vrisekoop N, Germain RN. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity (2013) 38:263-74. doi:10.1016/j.immuni.2012.09.011
27. Nelson RW, Beisang D, Tubo NJ, Dileepan T, Wiesner DL, Nielsen K, et al. T cell receptor cross-reactivity between similar foreign and self peptides influences naïve cell population size and autoimmunity. Immunity (2014) 42(1):95-107. doi:10.1016/j.immuni.2014.12.022
28. Fazilleau N, McHeyzer-Williams LJ, Rosen H, McHeyzer-Williams MG. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol (2009) 10:375-84. doi:10.1038/ni.1704
29. Puech PH, Nevoltris D, Robert P, Limozin L, Boyer C, Bongrand P. Force measurements of TCR/pMHC recognition at T cell surface. PLoS One (2011) 6(7):e22344. doi:10.1371/journal.pone.0022344
30. Chervin AS, Stone JD, Holler PD, Bai A, Chen J, Eisen HN, et al. The impact of TCR-binding properties and antigen presentation format on T cell responsiveness. J Immunol (2009) 183:1166-78. doi:10.4049/jimmunol.0900054
31. Daniels MA, Jameson SC. Critical role for CD8 in T cell receptor binding and activation by peptide/major histocompatibility complex multimers. J Exp Med (2000) 191:335-46. doi:10.1084/jem.191.2.335
32. Artyomov MN, Lis M, Devadas S, Davis MM, Chakraborty AK. CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery. Proc Natl Acad Sci U S A (2010) 107:16916-21. doi:10.1073/pnas.1010568107
33. Wooldridge L, van den Berg HA, Glick M, Gostick E, Laugel B, Hutchinson SL, et al. Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface. J Biol Chem (2005) 280:27491-501. doi:10.1074/jbc.M500555200
34. Jiang N, Huang J, Edwards LJ, Liu B, Zhang Y, Beal CD, et al. Two-stage cooperative T cell receptor-peptide major histocompatibility complex-CD8 trimolecular interactions amplify antigen discrimination. Immunity (2011) 34:13-23. doi:10.1016/j.immuni.2010.12.017
35. Garcia KC, Scott CA, Brunmark A, Carbone FR, Peterson PA, Wilson IA, et al. CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes. Nature (1996) 384:356-8. doi:10.1038/384577a0
36. Wyer JR, Willcox BE, Gao GF, Gerth UC, Davis SJ, Bell JI, et al. T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics. Immunity (1999) 10:219-25. doi:10.1016/S1074-7613(00)80022-9
37. Slifka MK, Whitton JL. Functional avidity maturation of CD8(+) T cells without selection of higher affinity TCR. Nat Immunol (2001) 2:711-7. doi:10.1038/90650
38. Holler PD, Kranz DM. Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity (2003) 18:255-64. doi:10.1016/S1074-7613(03)00019-0
39. Laugel B, van den Berg HA, Gostick E, Cole DK, Wooldridge L, Boulter J, et al. Different T cell receptor affinity thresholds and CD8 coreceptor dependence govern cytotoxic T lymphocyte activation and tetramer binding properties. J Biol Chem (2007) 282:23799-810. doi:10.1074/jbc.M700976200
40. Harding S, Lipp P, Alexander DR. A therapeutic CD4 monoclonal antibody inhibits TCR-zeta chain phosphorylation, zeta-associated protein of 70-kDa Tyr319 phosphorylation, and TCR internalization in primary human T cells. J Immunol (2002) 169:230-8. doi:10.4049/jimmunol.169.1.230
41. Pullar CE, Morris PJ, Wood KJ. Altered proximal T-cell receptor signalling events in mouse CD4+ T cells in the presence of anti-CD4 monoclonal antibodies: evidence for reduced phosphorylation of Zap-70 and LAT. Scand J Immunol (2003) 57:333-41. doi:10.1046/j.1365-3083.2003.01241.x
42. Kamperschroer C, Quinn DG. Quantification of epitope-specific MHC class-II-restricted T cells following lymphocytic choriomeningitis virus infection. Cell Immunol (1999) 193:134-46. doi:10.1006/cimm.1999.1458
43. Harrington LE, Most Rv RV, Whitton JL, Ahmed R. Recombinant vaccinia virus-induced T-cell immunity: quantitation of the response to the virus vector and the foreign epitope. J Virol (2002) 76:3329-37. doi:10.1128/JVI.76.7.3329-3337.2002
44. Varga SM, Welsh RM. Detection of a high frequency of virus-specific CD4+ T cells during acute infection with lymphocytic choriomeningitis virus. J Immunol (1998) 161:3215-8.
45. Murali-Krishna K, Altman JD, Suresh M, Sourdive DJD, Zajac AJ, Miller JD, et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity (1998) 8:177-87. doi:10.1016/S1074-7613(00)80470-7
46. Williams MA, Ravkov EV, Bevan MJ. Rapid culling of the CD4+ T cell repertoire in the transition from effector to memory. Immunity (2008) 28:533-45. doi:10.1016/j.immuni.2008.02.014
47. Martinez RJ, Zhang N, Thomas SR, Nandiwada SL, Jenkins MK, Binstadt BA, et al. Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells. J Immunol (2012) 188:170-81. doi:10.4049/jimmunol.1101311
48. McDermott DS, Varga SM. Quantifying antigen-specific CD4 T cells during a viral infection: CD4 T cell responses are larger than we think. J Immunol (2011) 187:5568-76. doi:10.4049/jimmunol.1102104
49. Viola A, Lanzavecchia A. T cell activation determined by T cell receptor number and tunable thresholds. Science (1996) 273:104-6. doi:10.1126/science.273.5271.104
50. Valitutti S, Müller S, Cella M, Padovan E, Lanzavecchia A. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature (1995) 375:148-51. doi:10.1038/375148a0
51. Davis SJ, van der Merwe PA. The kinetic-segregation model: TCR triggering and beyond. Nat Immunol (2006) 7:803-9. doi:10.1038/ni1369
52. Anton van der Merwe P, Davis SJ, Shaw AS, Dustin ML. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin Immunol (2000) 12:5-21. doi:10.1006/smim.2000.0203
53. Kalergis AM, Boucheron N, Doucey MA, Palmieri E, Goyarts EC, Vegh Z, et al. Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat Immunol (2001) 2:229-34. doi:10.1038/85286
54. Sugawara T, Moriguchi T, Nishida E, Takahama Y. Differential roles of ERK and p38 MAP kinase pathways in positive and negative selection of T lymphocytes. Immunity (1998) 9:565-74. doi:10.1016/S1074-7613(00)80639-1
55. Mariathasan S, Zakarian A, Bouchard D, Michie AM, Zuniga-Pflucker JC, Ohashi PS. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J Immunol (2001) 167:4966-73. doi:10.4049/jimmunol.167.9.4966
56. Fischer AM, Katayama CD, Pagès G, Pouysségur J, Hedrick SM. The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity (2005) 23:431-43. doi:10.1016/j.immuni.2005.08.013
57. McNeil LK, Starr TK, Hogquist KA. A requirement for sustained ERK signaling during thymocyte positive selection in vivo. Proc Natl Acad Sci U S A (2005) 102:13574-9. doi:10.1073/pnas.0505110102
58. Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F, Brzostek J, et al. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature (2013) 504:441-5. doi:10.1038/nature12718
59. Stepanek O, Prabhakar AS, Osswald C, King CG, Bulek A, Naeher D, et al. Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell (2014) 159:333-45. doi:10.1016/j.cell.2014.08.042
60. Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X, Mueller DL, et al. Murine thymic selection quantified using a unique method to capture deleted T cells. Proc Natl Acad Sci U S A (2013) 110:4679-84. doi:10.1073/pnas.1217532110
61. Fulton RB, Hamilton SE, Xing Y, Best JA, Goldrath AW, Hogquist KA, et al. The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8+ T cells to respond to foreign antigens. Nat Immunol (2014) 16:107-17. doi:10.1038/ni.3043
62. Bettini M, Blanchfield L, Castellaw A, Zhang Q, Nakayama M, Smeltzer MP, et al. TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential. J Immunol (2014) 193:571-9. doi:10.4049/jimmunol.1400043
63. Xing Y, Jameson SC, Hogquist KA. Thymoproteasome subunit-ß5T generates peptide-MHC complexes specialized for positive selection. Proc Natl Acad Sci U S A (2013) 110:6979-84. doi:10.1073/pnas.1222244110
64. Persaud SP, Parker CR, Lo W-L, Weber KS, Allen PM. Intrinsic CD4+ T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC. Nat Immunol (2014) 15:266-74. doi:10.1038/ni.2822
65. Hogquist KA, Jameson SC. The self-obsession of T cells: how TCR signaling thresholds affect fate "decisions" and effector function. Nat Immunol (2014) 15:815-23. doi:10.1038/ni.2938
66. Brownlie RJ, Zamoyska R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol (2013) 13:257-69. doi:10.1038/nri3403
67. Rosenthal KM, Edwards LJ, Sabatino JJ, Hood JD, Wasserman HA, Zhu C, et al. Low 2-dimensional CD4 T cell receptor affinity for myelin sets in motion delayed response kinetics. PLoS One (2012) 7:e32562. doi:10.1371/journal.pone.0032562
68. Stefanová I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol (2003) 4:248-54. doi:10.1038/ni895
69. Salmond RJ, Brownlie RJ, Morrison VL, Zamoyska R. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Nat Immunol (2014) 15:875-83. doi:10.1038/ni.2958
70. Hebeisen M, Baitsch L, Presotto D, Baumgaertner P, Romero P, Michielin O, et al. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J Clin Invest (2013) 123:1044-65. doi:10.1172/JCI65325
71. Liu B, Chen W, Evavold BD, Zhu C. Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell (2014) 157:357-68. doi:10.1016/j.cell.2014.02.053
72. Kumar D, Feng Y, Mallis RJ, Li X, Keskin DB, Hussey RE, et al. Force-dependent transition in the T-cell receptor ß-subunit allosterically regulates peptide discrimination and pMHC bond lifetime. Proc Natl Acad Sci U S A (2015) 112:1517-22. doi:10.1073/pnas.1424829112
73. Husson J, Chemin K, Bohineust A, Hivroz C, Henry N. Force generation upon T cell receptor engagement. PLoS One (2011) 6:e19680. doi:10.1371/journal.pone.0019680
74. Stritesky GL, Jameson SC, Hogquist KA. Selection of self-reactive T cells in the thymus. Annu Rev Immunol (2012) 30:95-114. doi:10.1146/annurev-immunol-020711-075035
75. Jenkins MK, Moon JJ. The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J Immunol (2012) 188:4135-40. doi:10.4049/jimmunol.1102661
76. Chu HH, Moon JJ, Takada K, Pepper M, Molitor JA, Schacker TW, et al. Positive selection optimizes the number and function of MHCII-restricted CD4+ T cell clones in the naive polyclonal repertoire. Proc Natl Acad Sci U S A (2009) 106:11241-5. doi:10.1073/pnas.0902015106
77. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, et al. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity (2007) 27:203-13. doi:10.1016/j.immuni.2007.07.007
78. Jenkins MK, Chu HH, McLachlan JB, Moon JJ. On the composition of the preimmune repertoire of T cells specific for peptide-major histocompatibility complex ligands. Annu Rev Immunol (2010) 28:275-94. doi:10.1146/annurev-immunol-030409-101253
79. Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. T cell receptor antagonist peptides induce positive selection. Cell (1994) 76:17-27. doi:10.1016/0092-8674(94)90169-4
80. Merkenschlager M, Benoist C, Mathis D. Evidence for a single-niche model of positive selection. Proc Natl Acad Sci U S A (1994) 91:11694-8. doi:10.1073/pnas.91.24.11694
81. Mingueneau M, Jiang W, Feuerer M, Mathis D, Benoist C. Thymic negative selection is functional in NOD mice. J Exp Med (2012) 209:623-37. doi:10.1084/jem.20112593
82. Ignatowicz L, Kappler J, Marrack P. The repertoire of T cells shaped by a single MHC/peptide ligand. Cell (1996) 84:521-9. doi:10.1016/S0092-8674(00)81028-4
83. Taniguchi RT, DeVoss JJ, Moon JJ, Sidney J, Sette A, Jenkins MK, et al. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc Natl Acad Sci U S A (2012) 109(20):7847-52. doi:10.1073/pnas.1120607109
84. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat Immunol (2003) 4:350-4. doi:10.1038/ni906
85. Yu W, Jiang N, Ebert PJR, Kidd BA, Muller S, Lund PJ, et al. Clonal deletion prunes but does not eliminate self-specific alpha beta CD8+ T lymphocytes. Immunity (2015) 42:929-41. doi:10.1016/j.immuni.2015.05.001
86. Quiel J, Caucheteux S, Laurence A, Singh NJ, Bocharov G, Ben-Sasson SZ, et al. Antigen-stimulated CD4 T-cell expansion is inversely and log-linearly related to precursor number. Proc Natl Acad Sci U S A (2011) 108:3312-7. doi:10.1073/pnas.1018525108
87. Zehn D, Bevan MJ. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity (2006) 25:261-70. doi:10.1016/j.immuni.2006.06.009
88. Knudson K, Goplen N, Cunningham C, Daniels M, Teixeiro E. Low-affinity T cells are programmed to maintain normal primary responses but are impaired in their recall to low-affinity ligands. Cell Rep (2013) 4:554-65. doi:10.1016/j.celrep.2013.07.008
89. King CG, Koehli S, Hausmann B, Schmaler M, Palmer E. T cell affinity regulates asymmetric division, effector cell differentiation, and tissue pathology. Immunity (2013) 37:709-20. doi:10.1016/j.immuni.2012.06.021
90. Vrisekoop N, Monteiro JP, Mandl JN, Germain RN. Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity (2014) 41:181-90. doi:10.1016/j.immuni.2014.07.007
91. Lee H-M, Bautista JL, Scott-Browne J, Mohan JF, Hsieh C-S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity (2012) 37:475-86. doi:10.1016/j.immuni.2012.07.009
92. Tubo NJ, Pagán AJ, Taylor JJ, Nelson RW, Linehan JL, Ertelt JM, et al. Single naive CD4(+) T cells from a diverse repertoire produce different effector cell types during infection. Cell (2013) 153:785-96. doi:10.1016/j.cell.2013.04.007
93. Keck S, Schmaler M, Ganter S, Wyss L, Oberle S, Huseby ES, et al. Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation. Proc Natl Acad Sci U S A (2014) 111:14852-7. doi:10.1073/pnas.1403271111
94. Baumgartner CK, Yagita H, Malherbe LP. A TCR affinity threshold regulates memory CD4 T cell differentiation following vaccination. J Immunol (2012) 189:2309-17. doi:10.4049/jimmunol.1200453
95. 4(+) T cell polarization in vivo. Immunity (2014) 41(1):63-74. doi:10.1016/j.immuni.2014.06.003
96. 4+ T cells. J Immunol (2002) 168:3825-32. doi:10.4049/jimmunol.168.8.3825
97. Caserta S, Kleczkowska J, Mondino A, Zamoyska R. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J Immunol (2010) 185:6545-54. doi:10.4049/jimmunol.1001867
98. O'Sullivan D, van der Windt GJW, Huang SC-C, Curtis JD, Chang C-H, Buck MD, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity (2014) 41:75-88. doi:10.1016/j.immuni.2014.06.005
99. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity (2011) 35:871-82. doi:10.1016/j.immuni.2011.09.021
100. Van der Windt GJW, O'Sullivan D, Everts B, Huang SC-C, Buck MD, Curtis JD, et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc Natl Acad Sci U S A (2013) 110:14336-41. doi:10.1073/pnas.1221740110
101. Man K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S, et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat Immunol (2013) 14:1155-65. doi:10.1038/ni.2710
102. Nikolich-Zugich J, Slifka MK, Messaoudi I. The many important facets of T-cell repertoire diversity. Nat Rev Immunol (2004) 4:123-32. doi:10.1038/nri1292
103. Moon JJ, Chu HH, Hataye J, Pagán AJ, Pepper M, McLachlan JB, et al. Tracking epitope-specific T cells. Nat Protoc (2009) 4:565-81. doi:10.1038/nprot.2009.9
104. Zarnitsyna VI, Evavold BD, Schoettle LN, Blattman JN, Antia R. Estimating the diversity, completeness, and cross-reactivity of the T cell repertoire. Front Immunol (2013) 4:485. doi:10.3389/fimmu.2013.00485
105. Langman RE, Cohn M. The E-T (elephant-tadpole) paradox necessitates the concept of a unit of B-cell function: the protection. Mol Immunol (1987) 24:675-97. doi:10.1016/0161-5890(87)90050-2
106. Wooldridge L, Ekeruche-Makinde J, van den Berg HA, Skowera A, Miles JJ, Tan MP, et al. A single autoimmune T cell receptor recognizes more than a million different peptides. J Biol Chem (2012) 287:1168-77. doi:10.1074/jbc.M111.289488
107. Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J, et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell (2014) 157:1073-87. doi:10.1016/j.cell.2014.03.047
108. Holler PD, Lim AR, Cho BK, Rund LA, Kranz DM. CD8(-) T cell transfectants that express a high affinity T cell receptor exhibit enhanced peptide-dependent activation. J Exp Med (2001) 194:1043-52. doi:10.1084/jem.194.8.1043
109. Donermeyer DL, Weber KS, Kranz DM, Allen PM. The study of high-affinity TCRs reveals duality in T cell recognition of antigen: specificity and degeneracy. J Immunol (2006) 177:6911-9. doi:10.4049/jimmunol.177.10.6911
110. Holler PD, Chlewicki LK, Kranz DM. TCRs with high affinity for foreign pMHC show self-reactivity. Nat Immunol (2003) 4:55-62. doi:10.1038/ni863
111. O'Sullivan JA, Zloza A, Kohlhapp FJ, Moore TV, Lacek AT, Dulin NO, et al. Priming with very low-affinity peptide ligands gives rise to CD8+ T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)ß-mediated suppression. Cancer Immunol Immunother (2011) 60:1543-51. doi:10.1007/s00262-011-1043-1
112. Khan N, Cobbold M, Cummerson J, Moss PAH. Persistent viral infection in humans can drive high frequency low-affinity T-cell expansions. Immunology (2010) 131:537-48. doi:10.1111/j.1365-2567.2010.03326.x
113. Lyman MA, Nugent CT, Marquardt KL, Biggs JA, Pamer EG, Sherman LA. The fate of low affinity tumor-specific CD8+ T cells in tumor-bearing mice. J Immunol (2005) 174:2563-72. doi:10.4049/jimmunol.174.5.2563
114. Rees W, Bender J, Teague TK, Kedl RM, Crawford F, Marrack P, et al. An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad Sci U S A (1999) 96:9781-6. doi:10.1073/pnas.96.17.9781
115. Srinivasan A, Foley J, McSorley SJ. Massive number of antigen-specific CD4 T cells during vaccination with live attenuated Salmonella causes interclonal competition. J Immunol (2004) 172:6884-93. doi:10.4049/jimmunol.172.11.6884
116. Majstoravich S, Zhang J, Nicholson-Dykstra S, Linder S, Friedrich W, Siminovitch KA, et al. Lymphocyte microvilli are dynamic, actin-dependent structures that do not require Wiskott-Aldrich syndrome protein (WASp) for their morphology. Blood (2004) 104:1396-403. doi:10.1182/blood-2004-02-0437
117. Sechi AS, Wehland J. Interplay between TCR signalling and actin cytoskeleton dynamics. Trends Immunol (2004) 25:257-65. doi:10.1016/j.it.2004.03.003
118. Miguel L, Owen DM, Lim C, Liebig C, Evans J, Magee AI, et al. Primary human CD4+ T cells have diverse levels of membrane lipid order that correlate with their function. J Immunol (2011) 186:3505-16. doi:10.4049/jimmunol.1002980
119. 4 and CD8 T cells require different membrane gangliosides for activation. Proc Natl Acad Sci U S A (2012) 109:E336-42. doi:10.1073/pnas.1114965109