Depletion of regulatory T cells in a hapten-induced inflammation model results in prolonged and increased inflammation driven by T cells

TY - JOUR

T1 - Depletion of regulatory T cells in a hapten-induced inflammation model results in prolonged and increased inflammation driven by T cells

AU - Christensen, A. D.

AU - Skov, Søren

AU - Kvist, P. H.

AU - Haase, C.

N1 - © 2014 Novo Nordisk A/S.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Regulatory T cells (Tregs ) are known to play an immunosuppressive role in the response of contact hypersensitivity (CHS), but neither the dynamics of Tregs during the CHS response nor the exaggerated inflammatory response after depletion of Tregs has been characterized in detail. In this study we show that the number of Tregs in the challenged tissue peak at the same time as the ear-swelling reaches its maximum on day 1 after challenge, whereas the number of Tregs in the draining lymph nodes peaks at day 2. As expected, depletion of Tregs by injection of a monoclonal antibody to CD25 prior to sensitization led to a prolonged and sustained inflammatory response which was dependent upon CD8 T cells, and co-stimulatory blockade with cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) suppressed the exaggerated inflammation. In contrast, blockade of the interleukin (IL)-10-receptor (IL-10R) did not further increase the exaggerated inflammatory response in the Treg -depleted mice. In the absence of Tregs , the response changed from a mainly acute reaction with heavy infiltration of neutrophils to a sustained response with more chronic characteristics (fewer neutrophils and dominated by macrophages). Furthermore, depletion of Tregs enhanced the release of cytokines and chemokines locally in the inflamed ear and augmented serum levels of the systemic inflammatory mediators serum amyloid (SAP) and haptoglobin early in the response.

AB - Regulatory T cells (Tregs ) are known to play an immunosuppressive role in the response of contact hypersensitivity (CHS), but neither the dynamics of Tregs during the CHS response nor the exaggerated inflammatory response after depletion of Tregs has been characterized in detail. In this study we show that the number of Tregs in the challenged tissue peak at the same time as the ear-swelling reaches its maximum on day 1 after challenge, whereas the number of Tregs in the draining lymph nodes peaks at day 2. As expected, depletion of Tregs by injection of a monoclonal antibody to CD25 prior to sensitization led to a prolonged and sustained inflammatory response which was dependent upon CD8 T cells, and co-stimulatory blockade with cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) suppressed the exaggerated inflammation. In contrast, blockade of the interleukin (IL)-10-receptor (IL-10R) did not further increase the exaggerated inflammatory response in the Treg -depleted mice. In the absence of Tregs , the response changed from a mainly acute reaction with heavy infiltration of neutrophils to a sustained response with more chronic characteristics (fewer neutrophils and dominated by macrophages). Furthermore, depletion of Tregs enhanced the release of cytokines and chemokines locally in the inflamed ear and augmented serum levels of the systemic inflammatory mediators serum amyloid (SAP) and haptoglobin early in the response.

KW - Acute Disease

KW - Animals

KW - Antibodies, Monoclonal

KW - CD8-Positive T-Lymphocytes

KW - Chronic Disease

KW - Cytokines

KW - Dermatitis, Contact

KW - Dinitrofluorobenzene

KW - Disease Models, Animal

KW - Female

KW - Haptoglobins

KW - Humans

KW - Immunoconjugates

KW - Inflammation

KW - Interleukin-2 Receptor alpha Subunit

KW - Lymph Nodes

KW - Lymphocyte Depletion

KW - Macrophages

KW - Mice

KW - Mice, Inbred BALB C

KW - Neutrophils

KW - Serum Amyloid A Protein

KW - T-Lymphocytes, Regulatory

U2 - 10.1111/cei.12466

DO - 10.1111/cei.12466

M3 - Journal article

C2 - 25302741

SN - 0964-2536

VL - 179

SP - 485

EP - 499

JO - Clinical and Experimental Immunology, Supplement

JF - Clinical and Experimental Immunology, Supplement

IS - 3

ER -