RESUMO
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
Assuntos
Linfócitos B , Proteínas de Ligação a DNA , Proteínas de Homeodomínio , Proteínas Nucleares , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Humanos , Tolerância Imunológica , Contagem de Linfócitos , Proteínas Nucleares/deficiênciaRESUMO
Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3ß kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3ß axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Ferroptose/imunologia , Memória Imunológica/imunologia , Longevidade/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/imunologia , Animais , Glicogênio Sintase Quinase 3 beta/imunologia , Peroxidação de Lipídeos/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos/métodos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/imunologiaRESUMO
CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis.
Assuntos
Moléculas de Adesão Celular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Homeostase , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação , Animais , Moléculas de Adesão Celular/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Proteínas da Matriz Extracelular/genética , Expressão Gênica , Técnicas de Inativação de Genes , Homeostase/imunologia , Humanos , Imunossenescência , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Via de Sinalização WntRESUMO
The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Dinâmica Mitocondrial/imunologia , Biomarcadores , Epigênese Genética , Epigenômica , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mitofagia , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Niacinamida/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Estresse Fisiológico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann-Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.
Assuntos
Inflamação/imunologia , Células T Matadoras Naturais/imunologia , Doenças de Niemann-Pick/genética , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/imunologia , Timo/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1d/metabolismo , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Terapia de Reposição de Enzimas , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esfingomielina Fosfodiesterase/genética , Esfingomielinas/metabolismoRESUMO
Intra-epithelial T cells make up a significant proportion of immune cells in the body, yet their development and function remain an enigma. In this issue of Immunity, Parsa et al. (2022) describe the differentiation and cross-protective function of CD4+ intra-epithelial T cells against enteric viruses.
Assuntos
Imunidade Inata , Intestino Delgado , Linfócitos T CD4-Positivos , Contagem de LinfócitosRESUMO
Metastatic ovarian cancer is a significant clinical challenge due in part to its poor response to immunotherapy. In a recent issue of Cancer Cell, Anandon et al. (2022) identify a population of stem-like tissue-resident memory T cells that are responsible for the bulk of anti-tumor T cell immunity, with insights into improving therapeutic response.
Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Animais , Imunoterapia , Contagem de Linfócitos , Lagoas , Microambiente TumoralRESUMO
Reinvigoration of exhausted CD8+ T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control. cDC1s were dispensable for Tpex cell expansion but provided an essential niche to promote Tpex cell maintenance, preventing their overactivation and T-cell-mediated immunopathology. Mechanistically, cDC1s insulated Tpex cells via MHC-I-dependent interactions to prevent their activation within other inflammatory environments that further aggravated their exhaustion. Our findings reveal that cDC1s maintain and safeguard Tpex cells within distinct anatomical niches to balance viral control, exhaustion, and immunopathology.
Assuntos
Linfócitos T CD8-Positivos , Células Dendríticas , Diferenciação Celular , Imunoterapia , Contagem de LinfócitosRESUMO
Immune checkpoint blockade has dramatically improved cancer therapy but remains ineffective for most colorectal tumors. In this issue of Immunity, Peuker et al. describe a microbiota-myeloid-tumor cell crosstalk that inhibits CD8+ T cells and promotes colorectal cancer progression.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias Colorretais , Linhagem Celular Tumoral , Humanos , Contagem de Linfócitos , Células Mieloides/patologia , Microambiente TumoralAssuntos
Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , Resfriado Comum/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Fatores Etários , COVID-19/patologia , Criança , Pré-Escolar , Humanos , Lactente , Contagem de Linfócitos , Fatores de Risco , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.
Assuntos
Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus/imunologia , Hipertensão/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , COVID-19 , Convalescença , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Complicações do Diabetes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/virologia , Progressão da Doença , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/virologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Monócitos/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
Adjuvanted vaccines afford invaluable protection against disease, and the molecular and cellular changes they induce offer direct insight into human immunobiology. Here we show that within 24 h of receiving adjuvanted swine flu vaccine, healthy individuals made expansive, complex molecular and cellular responses that included overt lymphoid as well as myeloid contributions. Unexpectedly, this early response was subtly but significantly different in people older than â¼35 years. Wide-ranging adverse clinical events can seriously confound vaccine adoption, but whether there are immunological correlates of these is unknown. Here we identify a molecular signature of adverse events that was commonly associated with an existing B cell phenotype. Thus immunophenotypic variation among healthy humans may be manifest in complex pathophysiological responses.
Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Adjuvantes Imunológicos , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoimunidade , Linfócitos B/imunologia , Linfócitos B/metabolismo , Análise por Conglomerados , Citocinas/sangue , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células Mieloides/imunologia , Células Mieloides/metabolismo , Fenótipo , Fatores de Tempo , Transcriptoma , Vacinação , Adulto JovemRESUMO
Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Assuntos
Imunidade Inata , Linfócitos/imunologia , Adolescente , Adulto , Animais , Biomarcadores , Criança , Modelos Animais de Doenças , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Subunidade gama Comum de Receptores de Interleucina/deficiência , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Janus Quinase 3/deficiência , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Linfopenia/sangue , Linfopenia/etiologia , Camundongos , Camundongos Knockout , Fenótipo , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/metabolismo , Imunodeficiência Combinada Severa/terapia , Pele/imunologia , Pele/patologiaRESUMO
ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.
Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Receptores CXCR4 , Verrugas , Humanos , Feminino , Receptores CXCR4/antagonistas & inibidores , Masculino , Doenças da Imunodeficiência Primária/tratamento farmacológico , Verrugas/tratamento farmacológico , Método Duplo-Cego , Adulto , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/tratamento farmacológico , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Adolescente , Adulto Jovem , Criança , Contagem de Linfócitos , Aminoquinolinas , Benzimidazóis , ButilaminasRESUMO
In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.
Assuntos
Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/imunologia , Linfopenia/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Animais , Infecções Assintomáticas/epidemiologia , Betacoronavirus/classificação , Betacoronavirus/isolamento & purificação , COVID-19 , China/epidemiologia , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Estado Terminal/epidemiologia , Progressão da Doença , Evolução Molecular , Feminino , Variação Genética , Genoma Viral/genética , Hospitalização/estatística & dados numéricos , Humanos , Mediadores da Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Contagem de Linfócitos , Linfopenia/complicações , Masculino , Pessoa de Meia-Idade , Pandemias , Filogenia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Síndrome do Desconforto Respiratório/complicações , SARS-CoV-2 , Linfócitos T/citologia , Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento , Virulência/genética , Eliminação de Partículas Virais , Adulto Jovem , Zoonoses/transmissão , Zoonoses/virologiaRESUMO
Despite the existence of central tolerance mechanisms, including clonal deletion and receptor editing to eliminate self-reactive B cells, moderately self-reactive cells still survive in the periphery (about 20% of peripheral B cells). These cells normally exist in a functionally silenced state called anergy; thus, anergy has been thought to contribute to tolerance by active-silencing of potentially dangerous B cells. However, a positive rationale for the existence of these anergic B cells has recently been suggested by discoveries that broadly neutralizing antibodies for HIV and influenza virus possess poly- and/or auto-reactivity. Given the conundrum of generating inherent holes in the immune repertoire, retaining weakly self-reactive BCRs on anergic B cells could allow these antibodies to serve as an effective defense against pathogens, particularly in the case of pathogens that mimic forbidden self-epitopes to evade the host immune system. Thus, anergic B cells should be brought into a silenced or activated state, depending on their contexts. Here, we review recent progress in our understanding of how the anergic B cell state is controlled in B cell-intrinsic and B cell-extrinsic ways.
Assuntos
Linfócitos B , Anergia Clonal , Epitopos , Humanos , Tolerância Imunológica , Contagem de LinfócitosRESUMO
Foxp3⺠regulatory T (Treg) cells are a crucial immunosuppressive population of CD4⺠T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2-dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways.