title: Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency.
abstract: Defects in IL-12 production or IL-12 responsiveness result in a vulnerability to infection with non-viral intracellular organisms, but the immunological mechanisms responsible for this susceptibility remain poorly understood. We present an immunological analysis of a patient with disseminated Salmonella enteritidis and a homozygous splice acceptor mutation in the IL-12Rbeta1-chain gene. This mutation resulted in the absence of IL-12Rbeta1 protein on PBMC and an inability of T cells to specifically bind IL-12 or produce IFN-gamma in response to either IL-12 or IL-23. The accumulation of memory (CD45R0(high)) CD4 T cells that were CCR7(high) (putative central memory cells) was normal or increased for age. Central memory CD4 T cells of the patient and age-matched controls were similar in having a low to undetectable capacity to produce IFN-gamma after polyclonal stimulation. In contrast, the patient had a substantial decrease in the number of CCR7(neg/dull) CD45R0(high) memory CD4 T cells (putative effector memory cells), and these differed from control cells in having a minimal ability to produce IFN-gamma after polyclonal stimulation. Importantly, tetanus toxoid-specific IFN-gamma production by PBMC from the patient was also significantly reduced compared with that in age-matched controls, indicating that signaling via the IL-12Rbeta1-chain is generally necessary for the in vivo accumulation of human memory CD4 T cells with Th1 function. These results are also consistent with a model in which the IL-12Rbeta1 subunit is necessary for the conversion of central memory CD4 T cells into effector memory cells.
authors.affiliation: Department of Pediatrics and the Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Cleary
authors.forename: Wenwei
authors.initials: W
authors.lastname: Tu
authors.forename: Andrea
authors.initials: A
authors.lastname: Enright
authors.forename: Thierry
authors.initials: T
authors.lastname: Giffon
authors.forename: Rene
authors.initials: R
authors.lastname: Dewaal-Malefyt
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gutierrez
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
mesh_terms: D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000172:deficiency / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D017354:Point Mutation; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053707:Receptors, Interleukin-12; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C508840:IL23A protein, human; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma