Biomedical subjects

Matthew C Walsh

Publications and source records attributed to Matthew C Walsh.

7 recordsLinked to original sources

PubMed2006

Osteoimmunology: interplay between the immune system and bone metabolism.

Studies of bone and the immune system have converged in recent years under the banner of osteoimmunology. The immune system is spawned in the bone marrow reservoir, and investigators now recognize that important niches also exist there for memory lymphocytes. At the same time, various factors produced during immune responses are capable of profoundly affecting regulation of bone. Mechanisms have evolved to prevent excessive interference by the immune system with bone homeostasis, yet pathologic bone loss is a common sequela associated with autoimmunity and cancer. There are also developmental links, or parallels, between bone and the immune system. Cells that regulate bone turnover share a common precursor with inflammatory immune cells and may restrict themselves anatomically, in part by utilizing a signaling network analogous to lymphocyte costimulation. Efforts are currently under way to further characterize how these two organ systems overlap and to develop therapeutic strategies that benefit from this understanding.

Animals↗

PubMed2005

Opposing roles for the cyclin-dependent kinase inhibitor p27kip1 in the control of CD4+ T cell proliferation and effector function.

Cell division drives T cell clonal expansion and differentiation, and is the result of concerted signaling from Ag, costimulatory, and growth factor receptors. How these mitogenic signals are coupled to the cell cycle machinery in primary T cells is not clear. We have focused on the role of p27kip1, a major cyclin-dependent kinase binding protein expressed by CD4+ T cells. Our studies using p27kip1 gene dosage demonstrate that early after activation, p27kip1 acts to promote, rather than inhibit, G1 to S phase progression within the first division cycle. However, throughout subsequent cell divisions p27kip1 behaves as a negative regulator, directly establishing the threshold amount of growth factor signaling required to support continued cell division. During this phase, signals from CD28 and IL-2R cooperate with the TCR to "tune" this threshold by inducing the degradation of p27kip1 protein, and we show that agents that block these pathways require elevated p27kip1 levels for their full antiproliferative activity. Finally, we show that p27kip1 opposes the development of CD4+ T cell effector function, and is required for the full development of anergy in response to a tolerizing stimulus. Our results suggest that p27kip1 plays a complex and important role in the regulation of cell division and effector function in primary CD4+ T cells.

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PubMed2004

The role of TRAF6 in signal transduction and the immune response.

Signals from the IL-1 receptor (IL-1R)/Toll-like receptor (TLR) family and TNF receptor (TNFR) superfamily are critical for regulating the function of antigen-presenting cells such as dendritic cells (DCs). It has been revealed that TNF receptor-associated factor 6 (TRAF6), a signaling adapter molecule common to the IL-1R/TLR family and TNFR superfamily, is important not only for DC maturation, cytokine production, and T cell stimulatory capacity of DCs in response to TLR ligands (e.g. lipopolysaccharide) or CD40 ligand, but also for the homeostasis of splenic DC subsets.

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PubMed2003

TNF receptor-associated factor 6 deficiency during hemopoiesis induces Th2-polarized inflammatory disease.

Toll-like receptors (TLR) initiate rapid innate immune responses by recognizing microbial products. These events in turn lead to the development of an efficient adaptive immune response through the up-regulation of a number of costimulatory molecules, including members of the TNF/TNFR superfamily, on the surface of an APC. TNFR-associated factor 6 (TRAF6) is a common signaling adapter used by members of both the TNFR and the TLR/IL-1R superfamilies, and as such plays a critical role in the development of immune responses. As TRAF6-deficient mice die prematurely, we generated chimeras reconstituted with TRAF6-deficient fetal liver cells to analyze functions of TRAF6 in vivo in the hemopoietic compartment. We found that TRAF6-deficient chimeras develop a progressive lethal inflammatory disease associated with massive organ infiltration and activation of CD4(+) T cells in a Th2-polarized phenotype, and a defect in IL-18 responsiveness. When recombination-activating gene 2(-/-) blastocysts were complemented with TRAF6-deficient embryonic stem cells, a marked elevation of activated CD4(+) T cells and progressive inflammatory disease were also observed. Moreover, T cell activation and lethal inflammation were not reversed in mixed chimeric mice generated from normal and TRAF6-deficient fetal liver cells. These results suggest that deletion of TRAF6 induces a dominant Th2-type polarized autoimmune response. Therefore, in addition to playing a critical role in innate and adaptive immunity, TRAF6 is likely to play a previously unrecognized role in the maintenance of self-tolerance.

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PubMed2003

TRAF6 is a critical factor for dendritic cell maturation and development.

IL-1 receptor (IL-1R)/Toll-like receptor (TLR) family and TNF receptor (TNFR) superfamily members are critical for regulating multiple aspects of dendritic cell (DC) biology. Several signaling pathways associated with each family utilize the adapter molecule, TRAF6, but its role in DCs is unclear. By examining TRAF6-deficient mice and bone marrow (BM) chimeras reconstituted with TRAF6-deficient fetal liver cells, we show that proper DC maturation requires TRAF6. In response to either microbial components or CD40L, TRAF6-deficient DCs fail to upregulate surface expression of MHCII and B7.2, or produce inflammatory cytokines. Moreover, LPS-treated TRAF6-deficient DCs do not exhibit an enhanced capacity to stimulate naive T cells. Interestingly, a major population of splenic DCs, the CD4(+)CD8alpha(-) subset, is nearly absent in both TRAF6-deficient mice and BM chimeras. Together these results indicate that TRAF6 regulates the critical processes required for maturation, activation, and development of DCs, the primary cellular bridge between innate and adaptive immunity.

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PubMed2002

Regulation of the subcellular localization of tumor necrosis factor receptor-associated factor (TRAF)2 by TRAF1 reveals mechanisms of TRAF2 signaling.

Tumor necrosis factor receptor-associated factor (TRAF)2 is a critical adaptor molecule for tumor necrosis factor (TNF) receptors in inflammatory and immune signaling. Upon receptor engagement, TRAF2 is recruited to CD40 and translocates to lipid rafts in a RING finger-dependent process, which enables the activation of downstream signaling cascades including c-Jun NH(2)-terminal kinase (JNK) and nuclear factor (NF)-kappaB. Although TRAF1 can displace TRAF2 and CD40 from raft fractions, it promotes the ability of TRAF2 activate signaling over a sustained period of time. Removal of the RING finger of TRAF2 prevents its translocation into detergent-insoluble complexes and renders it dominant negative for signaling. TRAF1(-/-) dendritic cells show attenuated responses to secondary stimulation by TRAF2-dependent factors and increased stimulus-dependent TRAF2 degradation. Replacement of the RING finger of TRAF2 with a raft-targeting signal restores JNK activation and association with the cyto-skeletal protein Filamin, but not NF-kappaB activation. These findings offer insights into the mechanism of TRAF2 signaling and identify a physiological role for TRAF1 as a regulator of the subcellular localization of TRAF2.

Amino Acid Sequence↗

PubMedDate not supplied

Biology of the TRANCE axis.

As the TNF and TNFR superfamilies have grown to more than two dozen combined members over the past 30 years, their involvement in interactions between immune cells, with regard to the events governing cellular differentiation, activation, and survival have been well established. The recently identified TNF superfamily cytokine, TRANCE (RANKL/OPGL/ODF/TNFSF11), which interacts with two receptors-one functional, TRANCE-R (RANK/TNFRSF11A), and one decoy, OPG (TNFRSF11B)-is a survival factor for activated dendritic cells, and may also be important for the maintenance of immune tolerance. TRANCE is also the key cytokine involved in osteoclast differentiation and activation, making TRANCE signaling crucial for proper bone homeostasis, and a potential therapeutic target in diseases such as osteoporosis, osteolytic metastatic cancer, arthritis, and periodontitis. Importantly, the positive role that TRANCE has in activating the immune system, appears to significantly contribute to pathologic bone loss. These observations have spurred intense study of the various ways in which the immune system can influence bone. Furthermore, TRANCE has also been demonstrated to play essential roles in the developmental processes leading to both lymph node formation, and the expansion and function of mammary glands during pregnancy and lactation. Thus, TRANCE is quickly emerging as a cytokine of significant importance to further understanding unique aspects of mammalian biology.

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