The CD4+CD28null and the regulatory CD4+CD25High T-cell phenotypes in patients with ulcerative colitis during active and quiescent disease, and following colectomy

doi:10.1016/j.cyto.2011.06.021

Cytokine

Volume 56, Issue 2, November 2011, Pages 466-470

https://doi.org/10.1016/j.cyto.2011.06.021 Get rights and content

Abstract

The CD4⁺CD25^High T-cell phenotype has an essential immunoregulatory role, while the CD4⁺CD28^null T-cell reflects immune pathology. We investigated the profiles of the CD4⁺CD25^High and the CD4⁺CD28^null T-cell phenotypes in patients with ulcerative colitis (UC) during active and quiescent phases as well as following colectomy. Fifty-nine UC patients, 34 active (UCa) and 25 quiescent (UCq) together with 19 healthy controls (HC) were included. Ten of 34 UCa patients underwent colectomy due to unremitting UC (UCo). Immunohistochemical phenotypic of the peripheral blood lymphocytes bearing CD4, CD25 or CD28 was done for analyzes by a multiparameter fluorescence activated cell sorting technique. The expression of the CD4⁺CD25^High phenotype was higher in UCq (P < 0.01) or UCo (P < 0.01) group vs UCa group. Further, the expression of the CD4⁺CD28^null phenotype in UCa or UCo group was higher than in the HC group (P < 0.05). However, the expression of the CD4⁺CD28^null phenotype up to 12 months after colectomy was not significantly different from the levels in the same patients during acute phase. Our impression is that a high CD4⁺CD25^High T-cell reflects alleviation of inflammation, while the expression of the CD4⁺CD28^null T-cell phenotype is an etiologic feature in UC patients, and is maintained after removing the affected colon.

Highlights

► This is the first study that has compared during active UC and following colectomy. ► There was evidence of Treg recovery following colectomy. ► The CD4⁺CD28^null T-cell level did not show association with UC clinical activity. ► The CD4⁺CD28^null T-cell phenotype was maintained after colectomy. ► CD28^null T-cell may be an etiologic marker to understand the immunopathogenesis of UC.

Introduction

Ulcerative colitis (UC) is a debilitating chronic inflammatory bowel disease (IBD) that afflicts millions of individuals throughout the world with symptoms which impair performance and quality of life [1], [2]. Factors, which initiate and perpetuate UC are not well understood yet. Accordingly, up to now medical therapy of UC has been empirical rather than being based on a sound understanding of disease pathology. The empirical approach to therapy might in large part account for intolerance, treatment failure and drug related adverse effects, adding to the disease complexities [1], [3], [4], [5].

Although the etiology of UC is not fully understood at present, there is convincing evidence that specific T-cell phenotypes together with several cytokines are important factors for the initiation and perpetuation of IBD [2], [6], [7]. Along these lines, the CD4⁺CD25^High T-cell phenotype, better known as the naturally arising regulatory T-cell is known to be intimately associated with physiologic immune function [6], [7], [8], [9]. In spite of this knowledge, an imbalanced T helper cell 1 (Th1) response in patients with Crohn’s disease (CD) and a Th2-like response in patients with UC have been cited as important mechanisms of immune pathology in IBD [10].

The CD25 is the alpha chain of the interleukin (IL)-2 receptor, a type I transmembrane protein present on activated T-cells, activated B-cells, some thymocytes, myeloid precursors and oligodendrocytes that are associate with the CD122 to form a heterodimer, a high-affinity receptor for IL-2 [11]. The CD4 bearing CD25 (CD4⁺CD25⁺) T-cells differentiate in the normal thymus as a functionally distinct CD4⁺CD25⁺ phenotype in the immune system [12]. The CD4 T-cells which strongly express CD25 are known to comprise 1–5% of peripheral CD4⁺ T-cells and are known as the CD4⁺CD25^High T-cells [8], [9]. Sakaguchi et al. [8] reported that the CD4⁺CD25⁺ T-cell depleted mice bear immunopathological features similar to human IBD [8].

Further, recently, we have been interested in the CD4 T-cells, which lack CD28 (CD4⁺CD28^null) [7]. Generally, the CD28 is present on most CD4 T-cells in healthy individuals, but a reduced expression in the elderly has been described [13]. The pathway for the CD28 with the ligand B7 is a second signal inducing T-cell activation [14]. Several investigators have shown that an over expression of CD4⁺CD28^null was associated with immune disorders [14], [15], [16], [17] like rheumatoid arthritis (RA) [15], Wegener’s granulomatosis (WG) [16]. Likewise, under expression of CD4⁺CD25^High has been suspected to contribute to dysregulated immune function [7] and conditions like systemic lupus erythematosus (SLE) [18], [19].

In the present study, our aim was to understand the profiles of both the CD4⁺CD25^High and the CD4⁺CD28^null during active UC, quiescent UC and following colectomy. The resection of the affected colon is expected to free the patient from the disease antigen. The expression profiles of the CD4⁺CD25^High T-cell phenotype at baseline and the CD4⁺CD28^null T-cell phenotype in the same patients before and up to 12 months after colectomy have been investigated and presented in this manuscript.

Section snippets

Patients

Subjects’ main demographic variables are presented in the Table 1. Fifty-nine patients, 28 male, 31 female, average age 37 years, range 16–71 years with a definitive diagnosis of UC were included. All patients had been treated at the Hyogo College of Medicine, Nishinomiya, Japan between April 2005 and March 2009. Nineteen age and gender matched healthy persons with no history of IBD and other allergic diseases were included as a control group (HC). Thirty-four of the 59 patients had active UC

The expression profile of the CD4⁺CD25^High T-cell phenotype

Fig. 1 is a typical FACS display showing the method used to determine the expression profiles of the regulatory CD4⁺CD25⁺ T-cells. Immunohistochemistry was applied for phenotypic determination of the target T-cells. The T-cells within each band were then measured by a multiparameter flow cytometry system. As shown, the CD4⁺CD25⁺ T-cell phenotype was separated into three sub-sets, low, intermediate and high representing CD4⁺CD25^Low, CD4⁺CD25^Intermediate and CD4⁺CD25^High, respectively [7].

Discussion

Knowledge accumulated in recent years has revealed that specific T lymphocytes have essential immunoregulatory roles, as exemplified by the CD4⁺CD25^High T-cell phenotype [7], [22]. However, it may look paradoxical that there are T-cell phenotypes which are associated with immune pathology, as exemplified by the CD4⁺CD28^null phenotype [7]. With this background in mind, we have been interested to understand the roles of CD4⁺CD25^High phenotype and its cousin, CD4⁺CD28^null phenotype in IBD [7], [21]

Disclosure

The authors acknowledge having no competing interest or funding interest in connection with the publication of this manuscript.

Acknowledgment

No external funding was received for this investigation.

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The CD4+CD28null and the regulatory CD4+CD25High T-cell phenotypes in patients with ulcerative colitis during active and quiescent disease, and following colectomy

Abstract

Highlights

Introduction

Section snippets

Patients

The expression profile of the CD4+CD25High T-cell phenotype

Discussion

Disclosure

Acknowledgment

Gastroenterology

Am J Pathol

Inflammatory bowel disease

Inflammatory bowel disease

N Engl J Med

How effective is current medical therapy for severe ulcerative and Crohn’s colitis? An analytic review of selected trials

J Clin Gastroenterol

Sulphasalazine – adverse effects and desensitization

Dig Dis Sci

How to do without steroids in inflammatory bowel disease

Inflamm Bowel Dis

Inflammatory bowel disease, past, present and the future: lessons from animal models

Gastroenterology

Demonstration of low-regulatory CD25HighCD4+ and high-pro-inflammatory CD28−CD4+ T-cell subsets in patients with ulcerative colitis: modified by selective granulocyte and monocyte adsorption apheresis

Dig Dis Sci

Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance

Immunol Rev

Naturally arising Foxp-3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self

Nat Immunol

Is the Th1/Th2 paradigm of immune regulation applicable to IBD?

Inflamm Bowel Dis

Localization of the gene encoding the human interleukin-2 receptor on chromosome 10

Science

Development and function of naturally occurring CD4+CD25+ regulatory T cells

J Leuk Biol

Altered CD28 and CD95 mRNA expression in peripheral blood mononuclear cells from elderly patients with primary non-small cell lung cancer

Chin Med J

CD4+CD7−CD28− T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity

J Clin Invest

CD28/B7 system of T cell costimulation

Annu Rev Immunol

CD28 negative T cells are enriched in granulomatous lesions of the respiratory tract in Wegener’s granulomatosis

Thorax

Active Crohn’s disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells

J Clin Immunol

Dysfunctional CD4+, CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells

Arthritis Rheum

The CD4⁺CD28^null and the regulatory CD4⁺CD25^High T-cell phenotypes in patients with ulcerative colitis during active and quiescent disease, and following colectomy

The expression profile of the CD4⁺CD25^High T-cell phenotype

Demonstration of low-regulatory CD25^HighCD4⁺ and high-pro-inflammatory CD28⁻CD4⁺ T-cell subsets in patients with ulcerative colitis: modified by selective granulocyte and monocyte adsorption apheresis

Immunologic tolerance maintained by CD25⁺CD4⁺ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance

Naturally arising Foxp-3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self

Development and function of naturally occurring CD4⁺CD25⁺ regulatory T cells

CD4⁺CD7⁻CD28⁻ T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity

Active Crohn’s disease patients show a distinctive expansion of circulating memory CD4⁺CD45RO⁺CD28^null T cells

Dysfunctional CD4⁺, CD25⁺ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells