RESUMEN
BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disease caused by genetic defects in the granule-mediated cytotoxic pathway. Success of hematopoietic cell transplantation, the only cure, is correlated with the extent of disease control before transplantation. Unfortunately, disease refractoriness and toxicities to standard chemotherapy-based regimens are fatal in a fraction of patients. Novel targeted immunotherapies, such as IFN-γ blocking antibodies or ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, are promising but only partially effective at controlling disease. OBJECTIVE: We asked whether combinations of cytokine-targeted therapies, using antibodies or JAK inhibitor, work synergistically to counteract HLH. METHODS: Genetically predisposed mice were infected and treated with distinct combinations of immunotherapies. Disease outcome was monitored and compared to monotherapies. RESULTS: We showed that inhibiting IL-6 or IL-18 signaling in combination with IFN-γ blockade or ruxolitinib did not increase disease control compared to anti-IFN-γ antibodies or ruxolitinib monotherapies. In contrast, clinically relevant doses of ruxolitinib combined with low doses of anti-IFN-γ blocking antibodies corrected cytopenias, prevented overt neutrophilia, limited cytokinemia, and resolved HLH immunopathology and symptomatology. CONCLUSIONS: Our findings demonstrate that IFN-γ blockade and ruxolitinib act synergistically to suppress HLH progression. This supports the use of combined cytokine-targeted therapies as a bridge to hematopoietic cell transplantation in severe familial hemophagocytic lymphohistiocytosis.
Asunto(s)
Linfohistiocitosis Hemofagocítica , Animales , Ratones , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Anticuerpos Bloqueadores/uso terapéutico , Interferón gamma/genética , Citocinas/metabolismoRESUMEN
BACKGROUND: Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes. OBJECTIVE: We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients. METHODS: We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT. RESULTS: Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, recent thymic emigrants, TCR excision circles, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion. CONCLUSIONS: Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfopenia , Inmunodeficiencia Combinada Grave , Humanos , Linfocitos T CD8-positivos , Agotamiento de Células T , Receptores de Antígenos de Linfocitos TRESUMEN
Exhaustion of CD8(+) T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain-dependent cytokines, on CD8(+) T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor ß (IL2Rß) chain is selectively maintained on CD8(+) T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8(+) T cells both in mice and humans. Genetic ablation of the IL2Rß chain on CD8(+) T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1(hi) effectors; and rescues memory T-cell development and responsiveness to IL-7-dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8(+) T-cell exhaustion during chronic viral infection.
Asunto(s)
Interleucina-15/genética , Subunidad beta del Receptor de Interleucina-2/genética , Interleucina-2/genética , Coriomeningitis Linfocítica/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Receptor 2 Celular del Virus de la Hepatitis A/genética , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Memoria Inmunológica , Interleucina-15/metabolismo , Interleucina-2/metabolismo , Subunidad beta del Receptor de Interleucina-2/inmunología , Interleucina-7/genética , Interleucina-7/inmunología , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/patología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/patogenicidad , Ratones , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
The ability to mount effective secondary responses is a cardinal feature of memory CD8(+) T cells. An understanding of the factors that regulate the generation and recall capacities of memory T cells remains to be ascertained. Several cues indicate that two highly related cytokines, IL-2 and IL-15, share redundant functions in this process. To establish their combined roles in memory CD8(+) T-cell development, maintenance, and secondary responses, we compared the outcome of adoptively transferred IL2Rß(+/-) or IL2Rß(-/-) CD8(+) T cells after an acute viral infection in mice. Our results demonstrate that both IL-2 and IL-15 signals condition the differentiation of primary and secondary short-lived effector cells by altering the transcriptional network governing lineage choices. These two cytokines also regulate the homeostasis of the memory T-cell pool, with effector memory CD8(+) T cells being the most sensitive to these two interleukins. Noticeably, the inability to respond to both cytokines limits the proliferation and survival of primary and secondary effectors cells, whereas it does not preclude potent cytotoxic functions and viral control either initially or upon rechallenge. Globally, these results indicate that lack of IL-2 and IL-15 signaling modulates the CD8(+) T-cell differentiation program but does not impede adequate effector functions.
Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Interleucina-15/farmacología , Interleucina-2/farmacología , Animales , Linfocitos T CD8-positivos/citología , Subunidad beta del Receptor de Interleucina-2/fisiología , Ratones , Ratones Endogámicos C57BLRESUMEN
UNLABELLED: Autoimmune hepatitis (AIH) is known as a T cell-mediated disease. However, AIH patients refractory to conventional treatment have been successfully treated with anti-CD20-mediated B-cell depletion. The aim of this project was to understand the immunological changes underlying the AIH remission caused by B-cell depletion in an experimental model of AIH. C57BL/6 AIH mice, xenoimmunized with DNA coding for human liver antigens, were treated with a single dose of depleting mouse anti-CD20 antibody at the peak of liver inflammation. Liver inflammation, alanine aminotransferase levels, chemokine (C-X-C) ligand 10 expression, and circulating B-cell, autoantibody, and total immunoglobulin G levels were monitored following depletion. T-cell and B-cell phenotype and function were characterized. Administration of a single dose of anti-CD20 resulted in a drastic reduction of liver inflammation accompanied by a significant reduction of alanine aminotransferase levels and of proinflammatory chemokine (C-X-C) ligand 10 expression. The treatment did not result in significant changes in total immunoglobulin G levels or autoantibodies. There were significantly more naive and less antigen-experienced CD4+ and CD8+ T cells, and T-cell proliferation was significantly reduced following anti-CD20 treatment. B cells served as antigen-presenting cells to CD4+ T cells. Anti-CD20 treatment also led to a profound reduction of T follicular helper cells. CONCLUSION: B cells play an active role in the pathogenesis of AIH in antigen presentation processes and the modulation of T-cell functions and influence the T follicular helper-cell population; this active role of B cells could explain the success of B-cell depletion for remission of AIH despite its classification as a T cell-mediated autoimmune liver disease.
Asunto(s)
Presentación de Antígeno , Linfocitos B/fisiología , Hepatitis Autoinmune/inmunología , Depleción Linfocítica , Linfocitos T/inmunología , Animales , Antígenos CD20/inmunología , Autoantígenos/inmunología , Citocinas/biosíntesis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BLRESUMEN
Some studies show eliminating senescent cells rejuvenate aged mice and attenuate deleterious effects of chemotherapy. Nevertheless, it remains unclear whether senescence affects immune cell function. We provide evidence that exposure of mice to ionizing radiation (IR) promotes the senescent-associated secretory phenotype (SASP) and expression of p16INK4a in splenic cell populations. We observe splenic T cells exhibit a reduced proliferative response when cultured with allogenic cells in vitro and following viral infection in vivo. Using p16-3MR mice that allow elimination of p16INK4a -positive cells with exposure to ganciclovir, we show that impaired T-cell proliferation is partially reversed, mechanistically dependent on p16INK4a expression and the SASP. Moreover, we found macrophages isolated from irradiated spleens to have a reduced phagocytosis activity in vitro, a defect also restored by the elimination of p16INK4a expression. Our results provide molecular insight on how senescence-inducing IR promotes loss of immune cell fitness, which suggest senolytic drugs may improve immune cell function in aged and patients undergoing cancer treatment.