Role of LAG-3 in Regulatory T Cells

AbstractRegulatory T cells (Tregs) limit autoimmunity but also attenuate the magnitude of antipathogen and antitumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Tregs in vivo requires identification of Treg-selective receptors. A comparative analysis of gene expression arrays from antigen-specific CD4+ T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg-selective expression of LAG-3, a CD4-related molecule that binds MHC class II. Antibodies to LAG-3 inhibit suppression by induced Tregs both in vitro and in vivo. Natural CD4+CD25+ Tregs express LAG-3 upon activation, which is significantly enhanced in the presence of effector cells, whereas CD4+CD25+ Tregs from LAG-3−/− mice exhibit reduced regulatory activity. Lastly, ectopic expression of LAG-3 on CD4+ T cells significantly reduces their proliferative capacity and confers on them suppressor activity toward effector T cells. We propose that LAG-3 marks regulatory T cell populations and contributes to their suppressor activity

Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen

SummaryTo understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland—but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance—allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation

Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma

In vitro differentiated CD8+ T cells have been the primary focus of immunotherapy of cancer with little focus on CD4+ T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4+ T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8+, B, natural killer (NK), and NKT cells. Proper activation of CD4+ T cells in vivo was important for tumor clearance, as naive tumor-specific CD4+ T cells could not completely treat tumor in lymphopenic common gamma chain (γc)–deficient hosts. γc signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4+ T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4+ T cells

A role for the transcription factor Helios in human CD4+CD25+ regulatory T cells

Gyotaejeon (Queen's Quarters), detail of stone pylons and raised base with ondol (underfloor heating); The largest of the Five Grand Palaces built by the Joseon dynasty, Gyeongbokgung served as the home of Kings of the Joseon [Chosŏn (medieval to modern) also known as Yi] dynasty, the Kings' households, as well as the government. The Yi dynasty ruled the Korean peninsula from 1392 to 1910, founded by Yi Sŏng-gye, posthumously known as King T’aejo (reigned 1392-1398). The palace was burnt and abandoned for three centuries following the Imjin War (1592-1598). In 1865-1872, all 7,700 rooms were restored along with 500 buildings over a 40 hectare site. In the early 20th century, much of the palace was systematically destroyed (all but 10 buildings) by Imperial Japan. Since the 1990s, the walled palace complex is gradually being reconstructed to its original form, with buildings built during Japanese occupation being pulled down, including the Japanese Government-General Building (removed 1996). By the end of 2009, it was estimated that approximately 40 percent of the structures that were standing before the Japanese occupation of Korea were restored or reconstructed; another 20 years of rebuilding is planned. Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 6/29/2015

LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems

Lymphocyte activation gene-3 (LAG-3) is a cell-surface molecule with diverse biologic effects on T cell function. We recently showed that LAG-3 signaling is important in CD4+ regulatory T cell suppression of autoimmune responses. Here, we demonstrate that LAG-3 maintains tolerance to self and tumor antigens via direct effects on CD8+ T cells using 2 murine systems. Naive CD8+ T cells express low levels of LAG-3, and expression increases upon antigen stimulation. Our data show increased levels of LAG-3 protein on antigen-specific CD8+ T cells within antigen-expressing organs or tumors. In vivo antibody blockade of LAG-3 or genetic ablation of the Lag-3 gene resulted in increased accumulation and effector function of antigen-specific CD8+ T cells within organs and tumors that express their cognate antigen. Most notably, combining LAG-3 blockade with specific antitumor vaccination resulted in a significant increase in activated CD8+ T cells in the tumor and disruption of the tumor parenchyma. A major component of this effect was CD4 independent and required LAG-3 expression by CD8+ T cells. Taken together, these data demonstrate a direct role for LAG-3 on CD8+ T cells and suggest that LAG-3 blockade may be a potential cancer treatment