Daan Pieren

185 General discussion and future perspectives 67. Schenkel, A. R. et al. The ly49 gene family. A brief guide to the nomenclature, genetics, and role in intracellular infection . Front. Immunol. 4, 90, doi:10.3389/fimmu.2013.00090 (2013). 68. Nakagawa, H. et al. New Insights Into the Biology of CD8 Regulatory T Cells . Adv. Immunol. 140, 1-20, doi:10.1016/bs.ai.2018.09.001 (2018). 69. Uhrberg, M. et al. Human diversity in killer cell inhibitory receptor genes . Immunity 7, 753-763, doi:10.1016/s1074-7613(00)80394-5 (1997). 70. Jiang, H. et al. HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes . J. Clin. Invest. 120, 3641-3650, doi:10.1172/ JCI43522 (2010). 71. Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition . Nat Commun 10, 2387, doi:10.1038/s41467-019-10335-5 (2019). 72. Akane, K. et al. CD8+CD122+CD49dlow regulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity . Proc. Natl. Acad. Sci. U. S. A. 113, 2460-2465, doi:10.1073/pnas.1525098113 (2016). 73. Lee, N. et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/ NKG2A . Proc. Natl. Acad. Sci. U. S. A. 95, 5199-5204, doi:10.1073/pnas.95.9.5199 (1998). 74. Michaelsson, J. et al. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition . J. Exp. Med. 196, 1403-1414, doi:10.1084/jem.20020797 (2002). 75. Quintana, F. J. et al. HSP60 as a target of anti-ergotypic regulatory T cells . PLoS One 3, e4026, doi:10.1371/journal.pone.0004026 (2008). 76. Bjorkstrom, N. K. et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education . Blood 116, 3853- 3864, doi:10.1182/blood-2010-04-281675 (2010). 77. Beziat, V. et al. NK cell terminal differentiation: correlated stepwise decrease of NKG2A and acquisition of KIRs . PLoS One 5, e11966, doi:10.1371/journal.pone .0011966 (2010 ). 78. van Stijn, A. et al. Human cytomegalovirus infection induces a rapid and sustained change in the expression of NK cell receptors on CD8+ T cells . J. Immunol. 180, 4550-4560, doi:10.4049/jimmunol.180.7.4550 (2008). 79. Brincks, E. L. et al. Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection . J. Immunol. 190, 3438-3446, doi:10.4049/ jimmunol.1203140 (2013). 80. Holderried, T. A. et al. Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection . Proc. Natl. Acad. Sci. U. S. A. 110, 21089-21094, doi:10.1073/ pnas.1320999110 (2013). 81. Schorer, M. et al. TIGIT limits immune pathology during viral infections . Nat Commun 11, 1288, doi:10.1038/s41467-020-15025-1 (2020). 82. Jin, J. H. et al. Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition . Cell. Mol. Immunol., doi:10.1038/s41423-020-0408-9 (2020). 83. Choo, J. A. et al. The immunodominant influenza A virus M158-66 cytotoxic T lymphocyte epitope exhibits degenerate class I major histocompatibility complex restriction in humans . J. Virol. 88, 10613-10623, doi:10.1128/JVI.00855-14 (2014). 84. Grifoni, A. et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals . Cell, doi:10.1016/j.cell.2020.05.015 (2020). 85. Johnson, S. C. et al. mTOR is a key modulator of ageing and age-related disease . Nature 493, 338-345, doi:10.1038/nature11861 (2013). 86. Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice . Elife 5, doi:10.7554/eLife.16351 (2016). 87. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice . Nature 460, 392-395, doi:10.1038/nature08221 (2009). 88. Chen, C. et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells . Sci Signal 2, ra75, doi:10.1126/scisignal.2000559 (2009). 89. Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly . Sci. Transl. Med. 6, 268ra179, doi:10.1126/scitranslmed.3009892 (2014). 6