RESUMO
Human immune system (HIS) mouse models provide a robust in vivo platform to study human immunity. Nevertheless, the signals that guide human lymphocyte differentiation in HIS mice remain poorly understood. Here, we have developed a novel Balb/c Rag2-/- Il2rg-/- SirpaNOD (BRGS) HIS mouse model expressing human HLA-A2 and -DR2 transgenes (BRGSA2DR2). When comparing BRGS and BRGSA2DR2 HIS mice engrafted with human CD34+ stem cells, a more rapid emergence of T cells in the circulation of hosts bearing human HLA was shown, which may reflect a more efficient human T-cell development in the mouse thymus. Development of CD4+ and CD8+ T cells was accelerated in BRGSA2DR2 HIS mice and generated more balanced B and T-cell compartments in peripheral lymphoid organs. Both B- and T-cell function appeared enhanced in the presence of human HLA transgenes with higher levels of class switched Ig, increased percentages of polyfunctional T cells and clear evidence for antigen-specific T-cell responses following immunization. Taken together, the presence of human HLA class I and II molecules can improve multiple aspects of human B- and T-cell homeostasis and function in the BRGS-based HIS mouse model.
Assuntos
Modelos Animais de Doenças , Linfopoese/imunologia , Camundongos Transgênicos , Linfócitos T , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Antígeno HLA-DR2/genética , Antígeno HLA-DR2/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
Humanized mice harboring human immune systems (HIS) represent a platform to study immune responses against pathogens and to screen vaccine candidates and novel immunotherapeutics. Innate and adaptive immune responses are suboptimal in HIS mice, possibly due to poor reconstitution of human antigen-presenting cells, including dendritic cells (DCs). DC homeostasis is regulated by cytokine availability, and Flt3-ligand (Flt3L) is one factor that conditions this process. Mouse myelopoiesis is essentially normal in most current HIS models. As such, developing mouse myeloid cells may limit human DC reconstitution by reducing available Flt3L and by cellular competition for specific "niches." To address these issues, we created a novel HIS model that compromises host myeloid cell development via deficiency in the receptor tyrosine kinase Flk2/Flt3. In Balb/c Rag2(-/-) Il2rg(-/-) Flt3(-/-) (BRGF) recipients, human conventional DCs and plasmacytoid DCs develop from hCD34(+) precursors and can be specifically boosted with exogenous Flt3L. Human DCs that develop in this context normally respond to TLR stimulation, and improved human DC homeostasis is associated with increased numbers of human NK and T cells. This new HIS-DC model should provide a means to dissect human DC differentiation and represents a novel platform to screen immune adjuvants and DC targeting therapies.
Assuntos
Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Tirosina Quinase 3 Semelhante a fms/deficiência , Adjuvantes Imunológicos , Animais , Homeostase , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/fisiologia , Células T Matadoras Naturais/fisiologia , Linfócitos T/fisiologia , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Several cytokines (including IL-2, IL-7, IL-15, and IL-21) that signal through receptors sharing the common gamma chain (gamma(c)) are critical for the generation and peripheral homeostasis of naive and memory T cells. Recently, we demonstrated that effector functions fail to develop in CD4(+) T cells that differentiate in the absence of gamma(c). To assess the role of gamma(c) cytokines in cell-fate decisions that condition effector versus memory CD8(+) T cell generation, we compared the response of CD8(+) T cells from gamma(c)(+) or gamma(c)(-) P14 TCR transgenic mice after challenge with lymphocytic choriomeningitis virus. The intrinsic IL-7-dependent survival defect of gamma(c)(-) naive CD8(+) T cells was corrected by transgenic expression of human Bcl-2. We demonstrated that although gamma(c)-dependent signals are dispensable for the initial expansion and the acquisition of cytotoxic functions following antigenic stimulation, they condition the terminal proliferation and differentiation of CD8(+) effector T cells (i.e., KLRG1(high) CD127(low) short-lived effector T cells) via the transcription factor, T-bet. Moreover, the gamma(c)-dependent signals that are critical for memory T cell formation are not rescued by Bcl2 overexpression. Together, these data reveal an unexpected divergence in the requirement for gamma(c) cytokines in the differentiation of CD4(+) versus CD8(+) cytotoxic T lymphocytes.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Memória Imunológica/imunologia , Subunidade gama Comum de Receptores de Interleucina/deficiência , Animais , Diferenciação Celular/genética , Citometria de Fluxo , Humanos , Processamento de Imagem Assistida por Computador , Memória Imunológica/genética , Subunidade gama Comum de Receptores de Interleucina/genética , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
The exact role of major histocompatibility complex (MHC) molecules in the peripheral survival of naive T cells is controversial, as some studies have suggested that they are critically required whereas others have suggested that they are not. Here we controlled for some of the features that differed among the earlier studies, and analyzed both the survival and expansion of naive CD4+ T cells transferred into MHC syngeneic, allogeneic, or MHC negative environments. We found that naive T cells transferred into MHC negative or allogeneic environments often fail to survive because of rejection and/or competition by natural killer (NK) cells, rather than failure to recognize a particular MHC allele. In the absence of NK cells, naive CD4+ T cells survived equally well regardless of the MHC type of the host. There was, however, an MHC requirement for extensive space-induced "homeostatic" expansion. Although the first few divisions occurred in the absence of MHC molecules, the cells did not continue to divide or transit to a CD44hi phenotype. Surprisingly, this MHC requirement could be satisfied by alleles other than the restricting haplotype. Therefore, space-induced expansion and survival are two different phenomena displaying different MHC requirements. Memory CD4+ T cells, whose survival and expansion showed no requirements for MHC molecules at all, dampened the space-induced expansion of naive cells, showing that the two populations are not independent in their requirements for peripheral niches.
Assuntos
Linfócitos T CD4-Positivos/fisiologia , Antígenos de Histocompatibilidade/fisiologia , Alelos , Animais , Sobrevivência Celular , Receptores de Hialuronatos/análise , Memória Imunológica , Células Matadoras Naturais/fisiologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Hepatic infections by hepatitis B virus (HBV), hepatitis C virus (HCV) and Plasmodium parasites leading to acute or chronic diseases constitute a global health challenge. The species tropism of these hepatotropic pathogens is restricted to chimpanzees and humans, thus model systems to study their pathological mechanisms are severely limited. Although these pathogens infect hepatocytes, disease pathology is intimately related to the degree and quality of the immune response. As a first step to decipher the immune response to infected hepatocytes, we developed an animal model harboring both a human immune system (HIS) and human hepatocytes (HUHEP) in BALB/c Rag2-/- IL-2Rγc-/- NOD.sirpa uPAtg/tg mice. The extent and kinetics of human hepatocyte engraftment were similar between HUHEP and HIS-HUHEP mice. Transplanted human hepatocytes were polarized and mature in vivo, resulting in 20-50% liver chimerism in these models. Human myeloid and lymphoid cell lineages developed at similar frequencies in HIS and HIS-HUHEP mice, and splenic and hepatic compartments were humanized with mature B cells, NK cells and naïve T cells, as well as monocytes and dendritic cells. Taken together, these results demonstrate that HIS-HUHEP mice can be stably (> 5 months) and robustly engrafted with a humanized immune system and chimeric human liver. This novel HIS-HUHEP model provides a platform to investigate human immune responses against hepatotropic pathogens and to test novel drug strategies or vaccine candidates.
Assuntos
Modelos Animais de Doenças , Hepatócitos/imunologia , Sistema Imunitário/fisiologia , Hepatopatias/imunologia , Camundongos , Animais , Linfócitos B/imunologia , Linfócitos B/fisiologia , Linfócitos B/transplante , Linhagem da Célula , Células Cultivadas , Quimerismo , Hepatócitos/parasitologia , Hepatócitos/virologia , Humanos , Sistema Imunitário/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Cinética , Hepatopatias/parasitologia , Hepatopatias/virologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Linfócitos T/imunologia , Linfócitos T/fisiologia , Linfócitos T/transplanteRESUMO
The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self-major histocompatibility complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2(-/-)gamma c(-/-) mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor alpha (IL-15R alpha) significantly augmented human NK cells. IL-15-IL-15R alpha complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16(+)KIR(+) NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56(hi)CD16(-)KIR(-) to CD56(lo)CD16(+)KIR(-), and finally to CD56(lo)CD16(+)KIR(+). These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15-responsive cells during immunotherapy strategies.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Interleucina-15/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antígenos de Diferenciação/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-15/administração & dosagem , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Receptores de Interleucina-15/agonistas , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Retroviridae/genética , Transdução Genética , Transplante Heterólogo , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
Cytokines signaling through receptors sharing the common gamma chain (gamma(c)), including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, are critical for the generation and peripheral homeostasis of B, T and NK cells. To identify unique or redundant roles for gamma(c) cytokines in naive CD4(+) T cells, we compared monoclonal populations of CD4(+) T cells from TCR-Tg mice that were gamma(c) (+), gamma(c) (-), CD127(-/-) or CD122(-/-). We found that gamma(c) (-) naive CD4(+) T cells failed to accumulate in the peripheral lymphoid organs and the few remaining cells were characterized by small size, decreased expression of MHC class I and enhanced apoptosis. By over-expressing human Bcl-2, peripheral naive CD4(+) T cells that lack gamma(c) could be rescued. Bcl-2(+) gamma(c) (-) CD4(+) T cells demonstrated enhanced survival characteristics in vivo and in vitro, and could proliferate normally in vitro in response to antigen. Nevertheless, Bcl-2(+) gamma(c) (-) CD4(+) T cells remained small in size, and this phenotype was not corrected by enforced expression of an activated protein kinase B. We conclude that gamma(c) cytokines (primarily but not exclusively IL-7) provide Bcl-2-dependent as well as Bcl-2-independent signals to maintain the phenotype and homeostasis of the peripheral naive CD4(+) T cell pool.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Homeostase/imunologia , Imunidade Inata/imunologia , Transdução de Sinais/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Tamanho Celular , Ativação Enzimática , Regulação da Expressão Gênica , Subunidade beta de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11c(lo)B220(+) cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207-213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214-219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor beta (IL-2Rbeta) chain but not those using the common gamma chain (gamma(c)) are necessary for their generation. By directly comparing Rag2(-/-)gamma(c)(-/y), Rag2(-/-)IL-2Rbeta(-/-), Rag2(-/-)IL-15(-/-), and Rag2(-/-)IL-2(-/-) mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46(+) cells are absent in Ncr1(gfp/+)gamma(c)(-/y) mice. Distinguishing features of IKDCs (CD11c(lo)B220(+)MHC-II(+)) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220(lo) versus B220(hi) NK1.1(+) NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1(+) NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II(+) NK1.1(+) cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1(+) cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11c(lo)B220(+) "IKDC-like" cells represent activated NK cells.
Assuntos
Antígeno CD11c/imunologia , Células Dendríticas/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Antígenos Comuns de Leucócito/imunologia , Ativação Linfocitária , Animais , Cruzamentos Genéticos , Antígenos de Histocompatibilidade Classe II/imunologia , Imunidade Celular , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/imunologiaRESUMO
After their initial antigen encounter in the secondary lymphoid organs, activated T cells must receive additional signals in the peripheral tissues to fully differentiate. Here, we provide evidence that gamma(c) cytokines are critical during this process. Using the Marilyn (Ml) T cell antigen receptor (TCR) transgenic model, we show that male skin grafts are tolerated in the absence of gamma(c), but that Ml CD4(+) T cells proliferate normally in response to antigen, traffic to the graft site and recruit an inflammatory response [including natural killer (NK) cells, neutrophils, and macrophages] that is independent of T cell gamma(c) expression. Whereas wild-type T cells demonstrate a progressive differentiation phenotype from the spleen to the tissues, skin-infiltrating effector T cells (CD44(hi)CD62L(lo)) from gamma(c)(-) mice were phenotypically abnormal with reduced ICOS, NKG2D, granzyme B, and IFN-gamma expression. These defects could be mapped to deficiencies in IL-2 and, surprisingly, IL-15. These results define a late checkpoint in T cell differentiation in the tissues where gamma(c) cytokines, including IL-15, authenticate CD4(+) T cell effector functions.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Animais , Feminino , Granzimas/biossíntese , Humanos , Receptores de Hialuronatos/biossíntese , Interferon gama/biossíntese , Interleucina-15/biossíntese , Subunidade beta de Receptor de Interleucina-2/biossíntese , Selectina L/biossíntese , Masculino , Camundongos , Camundongos Transgênicos , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores Imunológicos/biossíntese , Receptores de Células Matadoras NaturaisRESUMO
Natural killer (NK) cell development is thought to occur in the bone marrow. Here we identify the transcription factor GATA-3 and CD127 (IL-7R alpha) as molecular markers of a pathway of mouse NK cell development that originates in the thymus. Thymus-derived CD127+ NK cells repopulated peripheral lymphoid organs, and their homeostasis was strictly dependent on GATA-3 and interleukin 7. The CD127+ NK cells had a distinct phenotype (CD11b(lo) CD16- CD69(hi) Ly49(lo)) and unusual functional attributes, including reduced cytotoxicity but considerable cytokine production. Those characteristics are reminiscent of human CD56(hi) CD16- NK cells, which we found expressed CD127 and had more GATA-3 expression than human CD56+ CD16+ NK cells. We propose that bone marrow and thymic NK cell pathways generate distinct mouse NK cells with properties similar to those of the two human CD56 NK cell subsets.
Assuntos
Diferenciação Celular/imunologia , Fator de Transcrição GATA3/biossíntese , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Células Matadoras Naturais/citologia , Subpopulações de Linfócitos/citologia , Transdução de Sinais/imunologia , Timo/imunologia , Animais , Citocinas/biossíntese , Citotoxicidade Imunológica , Fator de Transcrição GATA3/genética , Humanos , Imunofenotipagem , Interleucina-7/fisiologia , Subunidade alfa de Receptor de Interleucina-7/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Timo/citologia , Timo/metabolismoRESUMO
Shigella flexneri, an enteroinvasive Gram-negative bacterium, is responsible for the worldwide endemic form of bacillary dysentery. The host response to primary infection is characterized by the induction of an acute inflammation, which is accompanied by polymorphonuclear cell (PMN) infiltration, resulting in massive destruction of the colonic mucosa. However, PMN play a major role in the recovery from primary infection, by restricting the bacterial infection at the intestinal mucosa. In this study, we assessed the roles for T and NK cells in the control of primary S. flexneri infection, using an alymphoid mouse strain (Rag null gamma(c) null) devoid of B, T, and NK cells. Using the mouse pulmonary model of Shigella infection, we showed that alymphoid Rag null gamma(c) null mice were highly susceptible to S. flexneri infection in comparison with wild-type (wt) mice. Whereas PMN recruitment upon infection was similar, macrophage recruitment and production of proinflammatory cytokines were significantly decreased in Rag null gamma(c) null mice compared with wt mice. Upon selective engraftment of Rag null gamma(c) null mice with polyclonal alphabeta T cells, but not with alphabeta T cells from IFN-gamma null , S. flexneri infection could be subsequently controlled. Rag null mice devoid of B and T cells but harboring NK cells could control infection. Local IFN-gamma production by T and NK cells recruited to the lung was demonstrated in S. flexneri-infected wt mice. These data demonstrate that both alphabeta T cells and NK cells contribute to the early control of S. flexneri infection through amplification of an inflammatory response. This cellular lymphocyte redundancy assures IFN-gamma production, which is central to innate immunity against Shigella infection.
Assuntos
Disenteria Bacilar/imunologia , Células Matadoras Naturais/imunologia , Shigella flexneri/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Disenteria Bacilar/genética , Disenteria Bacilar/prevenção & controle , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Imunidade Inata/genética , Mediadores da Inflamação/fisiologia , Interferon gama/biossíntese , Subunidade gama Comum de Receptores de Interleucina , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Células Matadoras Naturais/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/administração & dosagem , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplanteRESUMO
NK cells differentiate in adult mice from bone marrow hemopoietic progenitors. Cytokines, including those that signal via receptors using the common cytokine receptor gamma-chain (gamma(c)), have been implicated at various stages of NK cell development. We have previously described committed NK cell precursors (NKPs), which have the capacity to generate NK cells, but not B, T, erythroid, or myeloid cells, after in vitro culture or transfer to a fetal thymic microenvironment. NKPs express the CD122 Ag (beta chain of the receptors for IL-2/IL-15), but lack other mature NK markers, including NK1.1, CD49b (DX5), or members of the Ly49 gene family. In this report, we have analyzed the roles for gamma(c)-dependent cytokines in the generation of bone marrow NKP and in their subsequent differentiation to mature NK cells in vivo. Normal numbers of NKPs are found in gamma(c)-deficient mice, suggesting that NK cell commitment is not dependent on IL-2, IL-4, IL-7, IL-9, IL-15, or IL-21. Although IL-2, IL-4, and IL-7 have been reported to influence NK cell differentiation, we find that mice deficient in any or all of these cytokines have normal NK cell numbers, phenotype, and effector functions. In contrast, IL-15 plays a dominant role in early NK cell differentiation by maintaining normal numbers of immature and mature NK cells in the bone marrow and spleen. Surprisingly, the few residual NK cells generated in absence of IL-15 appear relatively mature, expressing a variety of Ly49 receptors and demonstrating lytic and cytokine production capacity.
Assuntos
Diferenciação Celular/imunologia , Proliferação de Células , Citocinas/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Receptores de Interleucina-7/fisiologia , Animais , Antígenos Ly/biossíntese , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Citocinas/biossíntese , Citocinas/deficiência , Citocinas/genética , Testes Imunológicos de Citotoxicidade , Células-Tronco Hematopoéticas/metabolismo , Subunidade gama Comum de Receptores de Interleucina , Interleucina-15/deficiência , Interleucina-15/genética , Interleucina-15/fisiologia , Interleucina-2/deficiência , Interleucina-2/genética , Interleucina-2/fisiologia , Interleucina-4/deficiência , Interleucina-4/genética , Interleucina-4/fisiologia , Interleucina-7/deficiência , Interleucina-7/genética , Interleucina-7/fisiologia , Células Matadoras Naturais/metabolismo , Lectinas Tipo C , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética , Receptores Semelhantes a Lectina de Células NKRESUMO
Several distinct classes of surface receptors can, on ligand binding, transmit signals that modulate the survival, proliferation, and apoptosis of peripheral B, T, and natural killer (NK) cells. At the population level, dynamic changes in lymphocyte cell numbers are strictly regulated to maintain a steady state, a process referred to as homeostasis. Although several studies have investigated the signals that regulate B- and T-cell homeostasis, little is known about the mechanisms that control the survival and proliferation of peripheral NK cells. Using an adoptive transfer system, we have investigated the role of gammac-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis. We observed that IL-15 plays a dominant role in the survival of peripheral NK cells, via maintenance of the antiapoptotic factor Bcl-2. IL-15 availability, however, also plays an important role because endogenous NK cells in the recipient mice influence the behavior of adoptively transferred NK cells. Finally, although NK cells bear functional inhibitory Ly49 receptors for MHC class I molecules, the presence or absence of specific ligands on host cells did not influence the survival or homeostatic expansion of donor NK cells.
Assuntos
Homeostase , Interleucina-15/fisiologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Transferência Adotiva , Animais , Antígenos Ly/fisiologia , Apoptose , Divisão Celular , Sobrevivência Celular , Deleção de Genes , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Subunidade gama Comum de Receptores de Interleucina , Interleucina-15/deficiência , Interleucina-15/genética , Interleucina-7/deficiência , Interleucina-7/genética , Interleucina-7/fisiologia , Células Matadoras Naturais/transplante , Lectinas Tipo C , Contagem de Linfócitos , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/fisiologia , Receptores Semelhantes a Lectina de Células NKRESUMO
Steady-state numbers of peripheral lymphocyte are tightly controlled. For conventional T cells, signals delivered through the interaction of the T cell receptor (TCR) with antigen-loaded MHC molecules are required for the peripheral survival of naive T cells and for their homeostatic expansion in lymphopenic hosts. Cytokines, including IL-7, are also essential for survival of peripheral naive T cells. CD1d-restricted, V alpha 14(+) natural killer (NK)-T cells are a specialized autoreactive T subset with immunoregulatory activity. The relative roles of TCR engagement and cytokine signaling in the peripheral homeostasis of V alpha 14(+) NK-T cells were investigated. After adoptive transfer, the survival and expansion of peripheral V alpha 14(+) NK-T cells was independent of CD1d expression in the host. In contrast, IL-15 (but not IL-7) was required for maintenance of peripheral CD1d-reactive V alpha 14(+) T cells. Comparison of V alpha 14(+) T cell transfers into NK-proficient vs. deficient hosts suggests that NK-T cells and NK cells compete for peripheral resources. Our results indicate that IL-15 maintains the homeostasis of peripheral V alpha 14(+) NK-T cells. In contrast, TCR "tickling" of NK-T cells, if it occurs under steady-state conditions, does not by itself provide a sufficient signal for their peripheral survival.