Control of Immune Responses by Antigen-Specific Regulatory T Cells Expressing the Folate Receptor

Abstract

Immune responses can be enhanced or dampened by differential manipulation of Foxp3-expressing CD25(+)CD4(+) natural regulatory T (Treg) cells versus other naive or activated T cells. By searching for a molecule capable of distinguishing these populations, we here found that natural Treg cells constitutively expressed high amounts of folate receptor 4 (FR4). The expression of FR4 and CD25 also separated antigen-stimulated CD4(+) non-Treg cells into the FR4(hi)CD25(-) and FR4(lo)CD25(+) populations, which were different in proliferation and cytokine secretion upon restimulation. These distinctions showed that antigenic stimulation activated and expanded antigen-specific natural Treg cells as well as effector and memory T cells. Accordingly, FR4(hi)CD25(+)CD4(+) T cells enriched from alloantigen-stimulated T cells suppressed graft rejection. Administration of FR4 monoclonal antibody specifically reduced Treg cells, provoking effective tumor immunity in tumor-bearing animals, whereas similar treatment of normal young mice elicited autoimmune disease. Thus, specific manipulation of FR4(hi)CD25(+)CD4(+) Treg cells helps control ongoing immune responses.

A dual role for autophagy in a murine model of lung cancer

“…Inactivation Tregs in vivo was performed as previously reported 42,43 . Briefly, anti-CD25 (500 mg per mouse, eBioscience, #16-0251), anti-FR4 (25 mg per mouse; Biolegend, #125102) or a rat IgG1 isotype control Ab (eBioscience, #16-4301; Biolegend, #400622) were injected once at day À 1 before AdCre inhalation.…”

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

“…Indeed, depletion of Treg with antibodies against CD25 or Folate receptor 4 significantly augmented anti-tumor immune responses in several preclinical mouse models. 29 , [36][37][38] However, as these markers are also expressed on activated CD4 þ FoxP3 -and CD8 þ T-cells such treatments may concomitantly diminish the effector arm of anti-tumor immunity. 28 , 39 This may account for the modest clinical effect and low reproducibility of these depletion strategies.…”

Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer

“…To date, various attempts have been made to reverse this immunosuppressive status using anti-CD25 antibody (35)(36)(37), inhibition of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathway (38), or anti-glucocorticoid-induced tumor necrosis receptor (GITR) family-related protein (39). Yamaguchi et al (40) reported that folate receptor 4 expression is also specific to Tregs and may be a candidate for selective Treg elimination. Furthermore, vaccination against FoxP3 was also previously attempted in vivo (41); thus, this FoxP3-targeted therapy may be used to treat patients with increased Treg numbers.…”