RESUMEN
Resident memory T (Trm) cells stably occupy tissues and cannot be sampled in superficial venous blood. Trm cells are heterogeneous but collectively constitute the most abundant memory T cell subset. Trm cells form an integral part of the immune sensing network, monitor for local perturbations in homeostasis throughout the body, participate in protection from infection and cancer, and likely promote autoimmunity, allergy, and inflammatory diseases and impede successful transplantation. Thus Trm cells are major candidates for therapeutic manipulation. Here we review CD8+ and CD4+ Trm ontogeny, maintenance, function, and distribution within lymphoid and nonlymphoid tissues and strategies for their study. We briefly discuss other resident leukocyte populations, including innate lymphoid cells, macrophages, natural killer and natural killer T cells, nonclassical T cells, and memory B cells. Lastly, we highlight major gaps in knowledge and propose ways in which a deeper understanding could result in new methods to prevent or treat diverse human diseases.
Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Asesinas Naturales/fisiología , Leucocitos/inmunología , Macrófagos/inmunología , Animales , Movimiento Celular , Humanos , Inmunidad Innata , Memoria Inmunológica , Especificidad de ÓrganosRESUMEN
Specialized subpopulations of CD4+ T cells survey major histocompatibility complex class II-peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4+ T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4+ T cell biology.
Asunto(s)
Linfocitos T CD4-Positivos , Células T de Memoria , Humanos , Memoria InmunológicaRESUMEN
Tissue-resident memory T (TRM) cells positively correlate with cancer survival, but the anti-tumor mechanisms underlying this relationship are not understood. This review reconciles these observations, summarizing concepts of T cell immunosurveillance, fundamental TRM cell biology, and clinical observations on the role of TRM cells in cancer and immunotherapy outcomes. We also discuss emerging strategies that utilize TRM-phenotype cells for patient diagnostics, staging, and therapy. Current challenges are highlighted, including a lack of standardized T cell nomenclature and our limited understanding of relationships between T cell markers and underlying tumor biology. Existing findings are integrated into a summary of the field while emphasizing opportunities for future research.
Asunto(s)
Memoria Inmunológica , Células T de Memoria , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Células T de Memoria/inmunología , Animales , Memoria Inmunológica/inmunología , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Linfocitos Infiltrantes de Tumor/inmunologíaRESUMEN
Many US immigrant populations develop metabolic diseases post immigration, but the causes are not well understood. Although the microbiome plays a role in metabolic disease, there have been no studies measuring the effects of US immigration on the gut microbiome. We collected stool, dietary recalls, and anthropometrics from 514 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants and 19 Karen individuals sampled before and after immigration, as well as from 36 US-born European American individuals. Using 16S and deep shotgun metagenomic DNA sequencing, we found that migration from a non-Western country to the United States is associated with immediate loss of gut microbiome diversity and function in which US-associated strains and functions displace native strains and functions. These effects increase with duration of US residence and are compounded by obesity and across generations.
Asunto(s)
Pueblo Asiatico , Emigración e Inmigración , Microbioma Gastrointestinal , Adulto , Bacteroides/aislamiento & purificación , Fibras de la Dieta/metabolismo , Emigrantes e Inmigrantes , Humanos , Metagenoma , Obesidad/epidemiología , Obesidad/microbiología , Prevotella/aislamiento & purificación , Estados UnidosRESUMEN
Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM cells, effector memory T cells and TRM cells on recall. Ex-TRM cells, former intestinal TRM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called on.
Asunto(s)
Plasticidad de la Célula/inmunología , Memoria Inmunológica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Diferenciación Celular/inmunología , Femenino , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa/inmunología , Memoria Inmunológica/inmunología , Vigilancia Inmunológica/inmunología , Membrana Mucosa/inmunología , Animales , Femenino , Microscopía Intravital , Ratones , Membrana Mucosa/citología , Piel/inmunologíaRESUMEN
As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on establishing natural and vaccine-induced immunity against this coronavirus and the disease, COVID-19, that it causes. In this Primer, we explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.
Asunto(s)
COVID-19/inmunología , Memoria Inmunológica , SARS-CoV-2/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Linfocitos B/inmunología , COVID-19/patología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Humanos , Inmunidad Heteróloga , Inmunidad InnataRESUMEN
Following antigen-driven expansion in lymph node, transforming growth factor-ß (TGFß) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFß -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFß was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFßR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFß represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epidermis/inmunología , Queratinocitos/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Unión Competitiva , Efecto Espectador , Microambiente Celular , Células Clonales , Memoria Inmunológica , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Transducción de Señal , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
Memory CD8 T cells protect against intracellular pathogens by scanning host cell surfaces; thus, infection detection rates depend on memory cell number and distribution. Population analyses rely on cell isolation from whole organs, and interpretation is predicated on presumptions of near complete cell recovery. Paradigmatically, memory is parsed into central, effector, and resident subsets, ostensibly defined by immunosurveillance patterns but in practice identified by phenotypic markers. Because isolation methods ultimately inform models of memory T cell differentiation, protection, and vaccine translation, we tested their validity via parabiosis and quantitative immunofluorescence microscopy of a mouse memory CD8 T cell population. We report three major findings: lymphocyte isolation fails to recover most cells and biases against certain subsets, residents greatly outnumber recirculating cells within non-lymphoid tissues, and memory subset homing to inflammation does not conform to previously hypothesized migration patterns. These results indicate that most host cells are surveyed for reinfection by segregated residents rather than by recirculating cells that migrate throughout the blood and body.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Memoria Inmunológica , Virus de la Coriomeningitis Linfocítica/fisiología , Monitorización Inmunológica , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD8-positivos/inmunología , Movimiento Celular , Inflamación/inmunología , Lectinas Tipo C/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
Resident memory T cells (TRM) comprise a subset of nonrecirculating memory T cells that remain positioned at common portals of reinfection. These include barrier tissues such as the mucosae and skin. TRM orchestrate the initial response to pathogens re-encountered at these locales, thereby accelerating protective immune responses.
Asunto(s)
Memoria Inmunológica , Linfocitos T/inmunología , Animales , Humanos , Linfocitos T/citologíaRESUMEN
Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1-3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime-boost-boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.
Asunto(s)
División Celular , Senescencia Celular , Longevidad , Activación de Linfocitos , Linfocitos T , Animales , Ratones , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Memoria Inmunológica , Longevidad/inmunología , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T/citología , Linfocitos T/inmunología , Senescencia Celular/inmunología , Senescencia Celular/fisiología , Inmunización Secundaria , Vacunación , Traslado Adoptivo , Factores de Tiempo , Infecciones/inmunología , Enfermedad Crónica , Epigénesis GenéticaRESUMEN
Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8(+) tissue-resident memory T cells (TRM cells) require active transforming growth factor-ß1 (TGF-ß) for epidermal residence. Here we found that integrins αvß6 and αvß8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-ß. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required αvß6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-ß, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-ß by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epidermis/inmunología , Mucosa Intestinal/inmunología , Queratinocitos/inmunología , Células de Langerhans/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/citología , Movimiento Celular , Células Epidérmicas , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunidad Mucosa , Integrinas/inmunología , Mucosa Intestinal/citología , Intestino Delgado/citología , Intestino Delgado/inmunología , Células de Langerhans/citología , Ratones , Ratones Noqueados , Visón , Reacción en Cadena de la Polimerasa , Células del Estroma , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/inmunologíaRESUMEN
Regulated activation of the cytokine TGF-ß by integrins αvß6 and αvß8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking αvß6 and αvß8 integrins (Itgb6-/-Itgb8fl/fl-K14-cre), the absence of epidermal-activated TGF-ß resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Integrinas/metabolismo , Queratinocitos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Virus Vaccinia/inmunología , Animales , Antígenos de Neoplasias/genética , Linfocitos T CD8-positivos/enzimología , Diferenciación Celular/inmunología , Citocinas/inmunología , Activación Enzimática , Femenino , Integrinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Piel/citología , Piel/inmunologíaRESUMEN
Considerable advances have been made in recent years in understanding the generation and function of memory T cells. Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Here we consider new developments in the field and focus on how emerging differences between memory cells with respect to their trafficking, metabolism, epigenetic regulation, and longevity may fail to fit into small groups of "memory subsets." Rather, the properties of individual memory T cells fall on a continuum within each of these and other parameters. We discuss how this continuum influences the way that the efficacy of vaccination is assessed, as well as the suitability of a memory population for protective immunity.
Asunto(s)
Memoria Inmunológica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Diferenciación Celular , Movimiento Celular , Epigenómica , Humanos , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/fisiologíaRESUMEN
Immunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T (Trm) cells remain parked in nonlymphoid tissues and often stably express CD69. We recently identified Trm cells within SLO, but the origin and phenotype of these cells remains unclear. Using parabiosis of "dirty" mice, we found that CD69 expression is insufficient to infer stable residence of SLO Trm cells. Restimulation of nonlymphoid memory CD8+ T cells within the skin or mucosa resulted in a substantial increase in bona fide Trm cells specifically within draining lymph nodes. SLO Trm cells derived from emigrants from nonlymphoid tissues and shared some transcriptional and phenotypic signatures associated with nonlymphoid Trm cells. These data indicate that nonlymphoid cells can give rise to SLO Trm cells and suggest vaccination strategies by which memory CD8+ T cell immunosurveillance can be regionalized to specific lymph nodes.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Ganglios Linfáticos/inmunología , Animales , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Femenino , Lectinas Tipo C/análisis , Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
In metazoans, specific tasks are relegated to dedicated organs that are established early in development, occupy discrete locations and typically remain fixed in size. The adult immune system arises from a centralized haematopoietic niche that maintains self-renewing potential1,2, and-upon maturation-becomes distributed throughout the body to monitor environmental perturbations, regulate tissue homeostasis and mediate organism-wide defence. Here we examine how immunity is integrated within adult mouse tissues, and address issues of durability, expansibility and contributions to organ cellularity. Focusing on antiviral T cell immunity, we observed durable maintenance of resident memory T cells up to 450 days after infection. Once established, resident T cells did not require the T cell receptor for survival or retention of a poised, effector-like state. Although resident memory indefinitely dominated most mucosal organs, surgical separation of parabiotic mice revealed a tissue-resident provenance for blood-borne effector memory T cells, and circulating memory slowly made substantial contributions to tissue immunity in some organs. After serial immunizations or cohousing with pet-shop mice, we found that in most tissues, tissue pliancy (the capacity of tissues to vary their proportion of immune cells) enables the accretion of tissue-resident memory, without axiomatic erosion of pre-existing antiviral T cell immunity. Extending these findings, we demonstrate that tissue residence and organ pliancy are generalizable aspects that underlie homeostasis of innate and adaptive immunity. The immune system grows commensurate with microbial experience, reaching up to 25% of visceral organ cellularity. Regardless of the location, many populations of white blood cells adopted a tissue-residency program within nonlymphoid organs. Thus, residence-rather than renewal or recirculation-typifies nonlymphoid immune surveillance, and organs serve as pliant storage reservoirs that can accommodate continuous expansion of the cellular immune system throughout life. Although haematopoiesis restores some elements of the immune system, nonlymphoid organs sustain an accrual of durable tissue-autonomous cellular immunity that results in progressive decentralization of organismal immune homeostasis.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Microambiente Celular , Homeostasis , Memoria Inmunológica , Vigilancia Inmunológica , Inmunidad Adaptativa , Animales , Femenino , Inmunidad Innata , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
Humans experience frequent respiratory infections. Immunology and vaccinology studies in mice are typically performed in naive specific pathogen-free animals responding to their very first respiratory challenge. We found that the first respiratory infection induces lifelong enlargement of the lung-draining mediastinal lymph nodes (medLNs). Furthermore, infection-experienced medLNs supported better naive T cell surveillance and effector responses to new unrelated infections that exhibited more biased accumulation and memory establishment within the lung. Moreover, we observed that weight loss induced by influenza infection was substantially reduced in mice that had recovered from a previous unrelated respiratory viral challenge. These data show that the lack of infectious history and corresponding medLN hypoplasia in specific pathogen-free mice alter their immune response to lung infections. Preclinical vaccination and immunology studies should consider the previous infectious experience of the model organism.
Asunto(s)
Pulmón , Ganglios Linfáticos , Infecciones por Orthomyxoviridae , Animales , Ratones , Ganglios Linfáticos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Pulmón/inmunología , Pulmón/virología , Pulmón/patología , Ratones Endogámicos C57BL , Organismos Libres de Patógenos Específicos , Linfocitos T/inmunología , Memoria Inmunológica/inmunología , Mediastino , Infecciones del Sistema Respiratorio/inmunologíaRESUMEN
CD8(+) T cells eliminate intracellular infections through two contact-dependent effector functions: cytolysis and secretion of antiviral cytokines. Here we identify the following additional function for memory CD8(+) T cells that persist at front-line sites of microbial exposure: to serve as local sensors of previously encountered antigens that precipitate innate-like alarm signals and draw circulating memory CD8(+) T cells into the tissue. When memory CD8(+) T cells residing in the female mouse reproductive tract encountered cognate antigen, they expressed interferon-γ (IFN-γ), potentiated robust local expression of inflammatory chemokines and induced rapid recruitment of circulating memory CD8(+) T cells. Anamnestic responses in front-line tissues are thus an integrated collaboration between front-line and circulating populations of memory CD8(+) T cells, and vaccines should establish both populations to maximize rapid responses.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Virus de la Coriomeningitis Linfocítica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos Virales/inmunología , Movimiento Celular/inmunología , Células Cultivadas , Femenino , Genitales Femeninos/inmunología , Interacciones Huésped-Patógeno , Interferón gamma/genética , Interferón gamma/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Quimera por TrasplanteRESUMEN
Cell-mediated immunity critically depends on the localization of lymphocytes at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells (T(RM) cells)) are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of T(RM) cells is unknown. We found that CD8(+) T(RM) cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P1, a receptor for sphingosine 1-phosphate). Forced expression of S1P1 prevented the establishment of T(RM) cells. Cytokines that induced a T(RM) cell phenotype (including transforming growth factor-ß (TGF-ß), interleukin 33 (IL-33) and tumor-necrosis factor) elicited downregulation of KLF2 expression in a pathway dependent on phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt, which suggested environmental regulation. Hence, regulation of KLF2 and S1P1 provides a switch that dictates whether CD8(+) T cells commit to recirculating or tissue-resident memory populations.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Regulación hacia Abajo/inmunología , Memoria Inmunológica/inmunología , Receptores de Lisoesfingolípidos/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Citometría de Flujo , Interleucina-33 , Interleucinas/farmacología , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/inmunología , Factores de Transcripción de Tipo Kruppel/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Lectinas Tipo C/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Receptores de Esfingosina-1-Fosfato , Transcripción Genética/efectos de los fármacos , Transcripción Genética/inmunología , Factor de Crecimiento Transformador beta/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2-dependent resident Th2 memory cells as drivers of lung allergic responses.