The different T lymphocyte populations are the focus of research on dogs. Newly discovered double-positive T cells are characterized and their role in immune defense and immunopathology is investigated.

Menschen, Mäuse und andere Tiere besitzen sie, allen voran Schweine, CD4/CD8 doppelt-positive T-Zellen. Nun wird die Rolle dieser Zellpopulation in Hunden erforscht. Foto: Doris Bismarck

Double-positive T-cells of the dog

CD4 and CD8 double-positive T-cells of the dog

Lymphocytes, the cells of acquired immunity, include B and T lymphocytes. While the B lymphocytes belong to the humoral (lat. humor = fluid) defence because they produce antibodies and release them into the blood, the T cells take on various tasks within the cell-mediated immunity. They can generally be divided into two subpopulations: CD4+ T cells and CD8+ T cells, i.e. cells that express either the CD4 or CD8 receptor (cluster of differentiation 4 or 8) on their surface. The CD4 receptor is a co-receptor that enables the binding of the T cell receptor to MHC-II (Major Histocompatibility Complex II) on antigen-presenting cells. CD4+ T-cells are also called T-helper cells because they contribute to the activation of macrophages, to the differentiation of B- to plasma cells, or to neutrophil recruitment by interacting with antigen-presenting cells and secreting various cytokines/transmitters. A subpopulation of the CD4+ T-helper cells (so-called regulatory T-cells) counteracts an overshooting of the immune system. CD8+ T-cells are known as cytotoxic T-cells and their function is to eliminate the body's own cells when they are virally infected or mutated into tumor cells.

It has long been assumed that T cells expressing both the CD4 and CD8 receptors on their surface, so-called CD4+CD8+ double-positive (dp) T cells, occur exclusively as immature developmental stages in the thymus. In the meantime, mature dp T cells have also been detected outside the thymus in various species: In humans for the first time by Blue et al. 1986 (1), also in pigs (2), chickens (3), monkeys (4), rats (5), and mice (6).  The detection in the peripheral blood of dogs was successful in the context of a research project from the Institute of Immunology of the Veterinary Medicine Faculty Leipzig (7).

References:

(1) Blue ML, J Immunol. 1986 Aug 15;137(4):1202-7
(2) Saalmüller A, Eur J Immunol. 1987 Sep;17(9):1297-301
(3) Luhtala M, Eur J Immunol. 1997 Jan;27(1):189-93
(4) Akari H, Int Immunol. 1997 Apr;9(4):591-7
(5) Takimoto H, Eur J Immunol. 1992 Jan;22(1):159-64
(6) Mosley RL, Int Immunol. 1990;2(4):361-5
(7) Schütze N, Vet Microbiol. 2009 Jun 12;137(3-4):260-7

Proposed and approved projects:

DFG:

  • "Phänotypische und funktionelle Analyse caniner peripherer CD4+CD8+ doppelt-positiver T-Zellen" (Projekt: 173176068 )

Further studies

Studies by the Institute of Immunology have shown that this T-cell subpopulation of peripheral blood can arise from both CD4+ T-helper cells and CD8+ cytotoxic T-cells and proliferates particularly well to viral restimulation (1-2). In addition, a large proportion is constitutively activated (3) and produces large amounts of the cytokine interferon-γ (IFN-γ) (4). IFN-γ is particularly important for the cellular immune response, for example in viral infections or tumor diseases. These properties make canine CD4+CD8+ dp T cells particularly interesting because they could be used therapeutically in the future. The Institute of Immunology was also able to show that canine CD4+CD8+ dp T cells of peripheral blood have not only effector function but also regulatory potential (4). This gives dp T cells a heterogeneous character that could be both protective and harmful to the body. Accordingly, it is not yet clear what role dp T-cells play in diseases such as autoimmune diseases or infections. To get to the bottom of this question, a subsequent study investigated the distribution of CD4+CD8+ dp T cells in different organs of healthy dogs. It was found that CD4+CD8+ dp T cells are found in mucosal organs such as the intestine or lungs as typical entry ports for infectious agents (5). The results of previous studies in healthy animals form the basis for current studies aimed at further understanding the physiological function of canine CD4+CD8+ dp T cells and highlighting their involvement in various diseases (e.g. inflammatory bowel disease in dogs), which may contribute to the development of alternative therapeutic strategies.
A summary on canine CD4+CD8+ dp T cells of peripheral blood can be found in the review of Buttlar et al. 2015 (6).

Proposed and approved projects:

DFG:

  • "Phänotypische und funktionelle Analyse caniner peripherer CD4+CD8+ doppelt-positiver T-Zellen " (Projekt: 173176068)

Publications:

(1) Schütze N, Vet Microbiol. 2009 Jun 12;137(3-4):260-7
(2) Bismarck D,  Vet Immunol Immunopathol. 2014 Dec 15;162(3-4):72-82
(3) Bismarck D, Vet Immunol Immunopathol. 2012 Oct 15;149(3-4):157-66
(4) Rothe K, Vet Immunol Immunopathol. 2017 Mar;185:48-56
(5) Rabiger FV, PLoS One. 2019 Mar 13;14(3):e0213597
(6) von Buttlar H, Vet Immunol Immunopathol. 2015 Dec 15;168(3-4):169-75

Cooperations:

  • Prof. Dr. Romy Heilmann (Leipzig, Germany)
  • Prof. Dr. Gabriele Köhler (Fulda, Germany)
  • Dr. Peter Moore DVM, PhD (Davis, California, USA)
  • Prof. Dr. Gerhard Oechtering (Leipzig, Germany)

Persons involved:

Dr. Maria Eschke
Friederike Rabiger
Anett Grohs

Alumni:

Dr. Heiner von Buttlar
Dr. Doris Bismarck
Dr. Kathrin Rothe

 

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