Chronic Pancreatitis Is Associated With Disease-Specific Regulatory T-Cell Responses

Background & Aims

Chronic pancreatitis is characterized by alternating phases of acute inflammation and quiescent disease. Involvement of T-cell responses has been suggested, but pancreatitis-specific T cells have not been described.

Methods

We characterized T-cell responses against pancreatitis, pancreatic carcinoma-associated antigens, and tetanus toxoid in the bone marrow, blood, and/or pancreatitis lesions of patients with pancreatitis, pancreatic cancer, and healthy individuals. T cells were functionally characterized by antigen-dependent secretion of interferon (IFN)-γ, interleukin (Il)-4, and IL-10, which indicate type 1, type 2, or regulatory T-cell responses, respectively. Regulatory T cells were characterized by multicolor flow cytometry. Isolated regulatory T cells were tested for their capacity to recognize pancreatitis-associated antigens and to suppress conventional T cells in an antigen-dependent manner. T cell-derived cytokines in tissue lesions were quantified by enzyme-linked immunosorbent assay.

Results

Chronic pancreatitis patients showed similar to pancreatic cancer patients and healthy individuals type 1 T-cell responses against tetanus toxoid; however, they exhibited strong IL-10-based T-cell responses against pancreatitis-associated but not pancreatic carcinoma-associated antigens. T cells from pancreatic cancer patients responded to pancreatic cancer-associated but not pancreatitis-associated antigens with IFN-γ secretion. Pancreatitis-specific IL-10 responses were mediated by IL-10⁺IFN-γ⁻FoxP3⁺ regulatory T cells, which were expanded in the blood, bone marrow, and pancreatitis lesions and possessed the potential to suppress the proliferation of autologous conventional T cells in an antigen-specific manner. Pancreatitis lesions, in comparison with pancreatic carcinomas, contained increased concentrations of IL-10 and reduced levels of IFN-γ, suggesting pancreatitis-specific activity of regulatory T cells in situ.

Conclusions

Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.

Keywords: Chronic Pancreatitis, Regulatory T Cells, Pancreatic Carcinoma

Abbreviations used in this paper: AIP, autoimmune pancreatitis, BM, bone marrow, CP, chronic pancreatitis, CP-L, lysate of chronic pancreatitis lesions, CPIL, CP tissue-infiltrating lymphocytes, DC, dentritic cells, ELISA, enzyme-linked immunosorbent assay, ELISPOT, enzyme-linked immunospot, HD, healthy donors, IFN, interferon, IL, interleukin, mAb, monoclonal antibodies, MHC, major histocompatibility complex, MUC, mucin, PaCa, primary pancreatic cancer, PB, blood, PBMC, peripheral blood mononuclear cells, TC, T cells, Tcon, conventional T cells depleted of CD4⁺CD25⁺ regulatory T cells, Tr1, T regulatory-1, Treg, T regulatory cells, TT, tetanus toxoid, Tu-L, lysate from pancreatic carcinoma tissue