Intercellular Adhesion Molecule-1 in T cell differentiation and as a target for peptide therapy of type 1 diabetes

CD4+ T cells are essential for proper function of the immune system. Many facets of an immune response are dependent on help from CD4+ T cells to become activated and exhibit effector function. Memory CD4+ T cells are a differentiated subset of T helper cells that give rise to long-lasted protective immunity. Differentiation to a memory phenotype from a naïve T cell that has never encountered antigen requires two signals. Costimulatory molecules send a second signal into naïve T cells that follows stimulation of the T cell receptor and greatly affects how naïve T cells activate and differentiate. The present work centers on the ability of the costimulatory molecule Intercellular Adhesion Molecile-1 (ICAM-1) to induce activation and differentiation of CD4+ naïve T cells to effector and memory phenotypes. We observed that costimulation through ICAM-1 generates a central memory-like population that is capable of migration to the lymph nodes and to a lesser extent the intestine. ICAM-1 costimulation is also capable of inducing memory differentiation after a short duration of signal but long-term costimulation is needed to generate a sizable population. In addition, costimulation of CD4+ naïve T cells from older individuals through ICAM-1 is able to produce memory cells more so than other costimulatory molecules. This suggesting that ICAM-1 could be utilized to help restore immune function during senescence. ICAM-1 and its ligand leukocyte function-associated antigen-1 (LFA-1) also provide targets for blocking self-reactive T cells in autoimmune diseases. Peptides against ICAM-1 and LFA-1 were used in the type I diabetes NOD mouse model. We observed a significant delay in symptoms with therapeutically treated mice compared to saline control mice and stopped T cell infiltration of the pancreatic islets. Additionally, T cells from treated mice were no longer able to respond to β-cell antigen indicating a shut down of the autoreactive immune response

Different immunological mechanisms govern protection from experimental stroke in young and older mice with recombinant TCR ligand therapy

Stroke is a leading cause of death and disability in the United States. The lack of clinical success in stroke therapies can be attributed, in part, to inadequate basic research on aging rodents. The current study demonstrates that recombinant TCR ligand therapy uses different immunological mechanisms to protect young and older mice from experimental stroke. In young mice, RTL1000 therapy inhibited splenocyte efflux while reducing frequency of T cells and macrophages in the spleen. Older mice treated with RTL1000 exhibited a significant reduction in inflammatory cells in the brain and inhibition of splenic atrophy. Our data suggest age specific differences in immune response to stroke that allow unique targeting of stroke immunotherapies

Choice of resident costimulatory molecule can influence cell fate in human naïve CD4+ T cell differentiation

With antigen stimulation, naïve CD4+ T cells differentiate to several effector or memory cell populations, and cytokines contribute to differentiation outcome. Several proteins on these cells receive costimulatory signals, but a systematic comparison of their differential effects on naïve T cell differentiation has not been conducted. Two costimulatory proteins, CD28 and ICAM-1, resident on human naïve CD4+ T cells were compared for participation in differentiation. Under controlled conditions, and with no added cytokines, costimulation through either CD3+CD28 or CD3+ICAM-1 induced differentiation to T effector and T memory cells. In contrast, costimulation through CD3+ICAM-1 induced differentiation to Treg cells whereas costimulation through CD3+CD28 did not

Elimination of T cell reactivity to pancreatic β cells and partial preservation of β cell activity by peptide blockade of LFA-1:ICAM-1 interaction in the NOD mouse model

In insulin dependent diabetes mellitus (T1D), self-reactive T cells infiltrate pancreatic islets and induce beta cell destruction and dysregulation of blood glucose. A goal is to control only the self-reactive T cells, leaving the remainder of the T cell population free to protect the host. One approach is blockade of the second signal for T cell activation while allowing the first (antigen-specific) signal to occur. This work proposes that small peptides that block interaction of second signals delivered through the counter receptors LFA-1:ICAM-1 will induce attacking T cells (receiving the antigen signal) to become anergic or undergo apoptosis. In NOD mice, the peptides eliminated T cell reactivity against pancreatic antigens and reduced cellular infiltration into islets, which retained stronger density of insulin staining at five weeks after cessation of therapy. In in vitro studies the peptides induced nonresponsiveness during activation of T cells from mice and from human peripheral blood