Identification of a Cytotoxic Form of Dimeric Interleukin-2 in Murine Tissues

Interleukin-2 (IL-2) is a multi-faceted cytokine, known for promoting proliferation, survival, and cell death depending on the cell type and state. For example, IL-2 facilitates cell death only in activated T cells when antigen and IL-2 are abundant. The availability of IL-2 clearly impacts this process. Our laboratory recently demonstrated that IL-2 is retained in blood vessels by heparan sulfate, and that biologically active IL-2 is released from vessel tissue by heparanase. We now demonstrate that heparanase digestion also releases a dimeric form of IL-2 that is highly cytotoxic to cells expressing the IL-2 receptor. These cells include “traditional” IL-2 receptor-bearing cells such as lymphocytes, as well as those less well known for IL-2 receptor expression, such as epithelial and smooth muscle cells. The morphologic changes and rapid cell death induced by dimeric IL-2 imply that cell death is mediated by disruption of membrane permeability and subsequent necrosis. These findings suggest that IL-2 has a direct and unexpectedly broad influence on cellular homeostatic mechanisms in both immune and non-immune systems

M tuberculosis in the adjuvant modulates time of appearance of CNS-specific effector T cells in the spleen through a polymorphic site of TLR2

DC deliver information regulating trafficking of effector T cells along T-cell priming. However, the role of pathogen-derived motives in the regulation of movement of T cells has not been studied. We hereinafter report that amount of M tuberculosis in the adjuvant modulates relocation of PLP139-151 specific T cells. In the presence of a low dose of M tuberculosis in the adjuvant, T cells (detected by CDR3 BV-BJ spectratyping, the so-called "immunoscope") mostly reach the spleen by day 28 after immunization ("late relocation") in the SJL strain, whereas T cells reach the spleen by d 14 with a high dose of M tuberculosis ("early relocation"). The C57Bl/6 background confers a dominant "early relocation" phenotype to F1 (SJL 7C57Bl/6) mice, allowing early relocation of T cells in the presence of low dose M tuberculosis. A single non-synonymous polymorphism of TLR2 is responsible for "early/late" relocation phenotype. Egress of T lymphocytes is regulated by TLR2 expressed on T cells. Thus, pathogens engaging TLR2 on T cells regulate directly T-cell trafficking, and polymorphisms of TLR2 condition T-cell trafficking upon a limiting concentration of ligand

I do not bid my lyre adieu [music] : a holiday song /

3831 (Publisher number). For voice and piano.; Pl. no.: 3831.; Engraved.; Also available online http://nla.gov.au/nla.mus-an10695153; Library's copy stamped: F. Ellard, Music Sellers, Sydney

Regulation of T Cell Homeostasis by Heparan Sulfate-Bound IL-2

Although IL-2 is commonly thought to promote proliferation of T lymphocytes, mice deficient in IL-2 exhibit splenomegaly, lymphocytosis, and autoimmunity, suggesting this cytokine may have a prominent role in T cell homeostasis. Since the number of T cells in the bloodstream and lymphoid organs is tightly controlled, it is likely that the availability of IL-2 must also be closely regulated. One mechanism altering the local availability of cytokines is association with heparan sulfate, a glycosaminoglycan found on cell surfaces and within extracellular matrices. Here we show that an association between IL-2 and heparan sulfate localizes IL-2 to lymphoid organs such as the spleen. We also show that IL-2, sequestered in this way, contributes to the activation of T lymphocytes and primes T lymphocytes for activation-induced cell death

Regulation of T Cell Homeostasis by Heparan Sulfate-Bound IL-2

Although IL-2 is commonly thought to promote proliferation of T lymphocytes, mice deficient in IL-2 exhibit splenomegaly, lymphocytosis, and autoimmunity, suggesting this cytokine may have a prominent role in T cell homeostasis. Since the number of T cells in the bloodstream and lymphoid organs is tightly controlled, it is likely that the availability of IL-2 must also be closely regulated. One mechanism altering the local availability of cytokines is association with heparan sulfate, a glycosaminoglycan found on cell surfaces and within extracellular matrices. Here we show that an association between IL-2 and heparan sulfate localizes IL-2 to lymphoid organs such as the spleen. We also show that IL-2, sequestered in this way, contributes to the activation of T lymphocytes and primes T lymphocytes for activation-induced cell death

Regional Manifestations and Control of the Immune System

Although immune responses are generally considered to be systemic, local events such as interaction of complement products with blood vessels and with inflammatory cells play a pivotal role in determining the nature and manifestations of immune responses. This paper will discuss how blood vessel physiology and immunity influence one another to reach homeostasis upon exposure to an infectious agent. We review new insights into the mechanisms by which the microenvironment of tissues protects against microbial invasion yet facilitates migration of leukocytes and ‘decides’ whether immunity or tolerance ensues and whether, in the face of immunity, protective responses or tissue injury ensues. These ‘decisions’ are made based on interaction of components of normal tissues such as proteoglycans and injured tissues such as cell-associated cytokines with receptors on immune cells and blood vessels

There are no Differences in Pretransplant Characteristics of Individuals Receiving Simultaneous Pancreas-Kidney Transplant and Individuals with Type 1 Diabetes Mellitus Receiving Living-Related Kidney Transplant

Simultaneous pancreas-kidney transplantation (SPK) recipients have longer survival compared to type 1 diabetes mellitus (DM1) cadaveric kidney recipients. However, DM1 living-related kidney transplant (KTX-LR) recipients have the same mortality as SPK recipients. It is unknown whether cardiovascular (CVD) risk factors pretransplant are similar between the two groups, SPK and DM1 KTX-LR. We analyzed pretransplant characteristics of SPK recipients (n = 39) and DM1 KTX-LR/living unrelated (LUR) recipients (KTX-LR/LUR, n = 20). In individuals who had multiple transplants, only pretransplant data from the first transplant was used. As all characteristics of KTX-LR/LUR recipients were the same, they were grouped for comparison with SPK. Pretransplant blood pressure (BP), body mass index, (BMI), hemoglobin A1c (A1c), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TG), serum creatinine, type and duration of dialysis, and duration of diabetes were compared between the two groups. Mean age at time of transplantation was 41 +/- 1 years (mean +/- SEM) for SPK versus 39 +/- 2 years for KTX-LR/LUR (P = NS). Pretransplant BP, BMI, duration of diabetes, TC, HDL, LDL, TG, and lipid agent use were not different between the groups. Pretransplant A1c was 7.8 +/- 0.3% for SPK recipients and 8.3 +/- 0.5% for KTX-LR/LUR recipients (P = NS). Pretransplant serum creatinine was higher in KTX-LR/LUR compared to SPK (7.9 +/- 0.6 mg/dL versus 5.4 +/- 0.5 mg/dL; P =.01). Except for serum creatinine, there were no significant differences in traditional CVD risk factors pretransplant. However, factors posttransplant in addition to better glucose control with SPK may still be different between SPK and KTX-LR/LUR groups