The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor.
T-cell responses are regulated by activating and inhibiting signals. CD28 and its homologue, cytotoxic T-lymphocyte antigen 4 (CTLA-4), are the primary regulatory molecules that enhance or inhibit T-cell activation, respectively. Recently it has been shown that inhibitory natural killer (NK) cell receptors (NKRs) are expressed on subsets of T cells. It has been proposed that these receptors may also play an important role in regulating T-cell responses. However, the extent to which the NKRs modulate peripheral T-cell homeostasis and activation in vivo remains unclear. In this report we show that NK cell inhibitory receptor Ly49A engagement on T cells dramatically limits T-cell activation and the resultant lymphoproliferative disorder that occurs in CTLA-4-deficient mice. Prevention of activation and expansion of the potentially autoreactive CTLA-4(-/-) T cells by the Ly49A-mediated inhibitory signal demonstrates that NKR expression can play an important regulatory role in T-cell homeostasis in vivo. These results demonstrate the importance of inhibitory signals in T-cell homeostasis and suggest the common biochemical basis of inhibitory signaling pathways in T lymphocytes.
Chambers
Cynthia A
CA
Department of Pathology, University of Massachusetts Medical School, Worcester, 01655, USA. cynthia.chambers@umassmed.edu
Kang
Joonsoo
J
Wu
Yongjian
Y
Held
Werner
W
Raulet
David H
DH
Allison
James P
JP
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000950:Antigens, Ly; D060908:CTLA-4 Antigen; D002352:Carrier Proteins / Q000276:immunology / Q000494:pharmacology; D006183:H-2 Antigens / Q000494:pharmacology; D064532:Histocompatibility Antigen H-2D; D006706:Homeostasis / Q000276:immunology*; D018796:Immunoconjugates; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic / Q000276:immunology*; D055630:Receptors, NK Cell Lectin-Like; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D060908:CTLA-4 Antigen; D002352:Carrier Proteins; C556707:Ctla4 protein, mouse; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D018796:Immunoconjugates; C527088:Klra1 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D000069594:Abatacept