Attenuation of Peripheral Regulatory T-Cell Suppression of Skin-Homing CD8+T Cells in Atopic Dermatitis
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Purpose: Cutaneous lymphocyte-associated antigen (CLA)-expressing CD8+T cells have been known to play an important role in the pathogenesis of atopic dermatitis(AD). However, the mechanisms underlying the loss of self-tolerance remainunclear. Regulatory T cells (Tregs) play a key role in the development of homeostasisin the immune system. We, therefore, hypothesized that a reduced ability of Tregs to inhibit autologous CD8+CLA+T cells might be underlying mechanism in AD. Materials and Methods: CD8+CLA+T cells and Tregs were obtained from the peripheral blood of AD patients and control volunteers. The frequenciesof CD8+CLA+T cells were evaluated. The proliferative responses of CD8+CLA+T cells were assessed by flow cytometry, and the levels of transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) in culture supernatants were detected by enzyme-linked immunosorbent assay. Results: Our results revealed higher frequency and increased expression of perforin and granzyme-B in peripheralCD8+CLA+T cells in AD, and lower inhibitory ability of Tregs on proliferation of CD8+CLA+T cells in AD. Meanwhile, the levels of TGF-β1 produced by Tregs were significantly lower in AD, and anti-TGF-β1 abolished such suppression. Conclusion: The attenuated inhibitory ability of Tregs on hyper-activated autologousCD8+CLA+T cells, mediated by TGF-β1, plays an important role in the pathogenesis of AD.
Abstract
Purpose: Cutaneous lymphocyte-associated antigen (CLA)-expressing CD8+T cells have been known to play an important role in the pathogenesis of atopic dermatitis(AD). However, the mechanisms underlying the loss of self-tolerance remainunclear. Regulatory T cells (Tregs) play a key role in the development of homeostasisin the immune system. We, therefore, hypothesized that a reduced ability of Tregs to inhibit autologous CD8+CLA+T cells might be underlying mechanism in AD. Materials and Methods: CD8+CLA+T cells and Tregs were obtained from the peripheral blood of AD patients and control volunteers. The frequenciesof CD8+CLA+T cells were evaluated. The proliferative responses of CD8+CLA+T cells were assessed by flow cytometry, and the levels of transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) in culture supernatants were detected by enzyme-linked immunosorbent assay. Results: Our results revealed higher frequency and increased expression of perforin and granzyme-B in peripheralCD8+CLA+T cells in AD, and lower inhibitory ability of Tregs on proliferation of CD8+CLA+T cells in AD. Meanwhile, the levels of TGF-β1 produced by Tregs were significantly lower in AD, and anti-TGF-β1 abolished such suppression. Conclusion: The attenuated inhibitory ability of Tregs on hyper-activated autologousCD8+CLA+T cells, mediated by TGF-β1, plays an important role in the pathogenesis of AD.
참고문헌 (32)
- Bieber T, "Atopic dermatitis", N Engl J Med, 358, pp.1483~1494 (2008)
- Hennino A, "CD8+ T cells are recruited early to allergen exposure sites in atopy patch test reactions in human atopic dermatitis", J Allergy Clin Immunol, 127, pp.1064~1067 (2011)
- Hennino A, "Skin-infiltrating CD8+ T cells initiate atopic dermatitis lesions", J Immunol, 178, pp.5571~5577 (2007)
- Sallusto F, "Two subsets of memory T lymphocytes with distinct homing potentials and effector functions", Nature, 401, pp.708~712 (1999)
- Akdis M, "Skin homing(cutaneous lymphocyte-associated antigen-positive)CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis", J Immunol, 163, pp.466~475 (1999)
- Teraki Y, "Increased circulating skin-homing cutaneous lymphocyte-associated antigen (CLA)+ type 2 cytokine-producing cells, and decreased CLA+ type 1 cytokine-producing cells in atopic dermatitis", Br J Dermatol, 143, pp.373~378 (2000)
- Sakaguchi S, "Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses", Annu Rev Immunol, 22, pp.531~562 (2004)
- Loser K, "In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity", Gene Ther, 12, pp.1294~1304 (2005)
- Fontenot JD, "Foxp3 programs the development and function of CD4+CD25+ regulatory T cells", Nat Immunol, 4, pp.330~336 (2003)
- Hori S, "Control of regulatory T cell development by the transcription factor Foxp3", Science, 299, pp.1057~1061 (2003)
- Verhagen J, "Absence of T-regulatory cell expression and function in atopic dermatitis skin", J Allergy Clin Immunol, 117, pp.176~183 (2006)
- Caproni M, "FoxP3-expressing T regulatory cells in atopic dermatitis lesions", Allergy Asthma Proc, 28, pp.525~528 (2007)
- Schnopp C, "Fox-P3-positive regulatory T cells are present in the skin of generalized atopic eczema patients and are not particularly affected by medium-dose UVA1 therapy", Photodermatol Photoimmunol Photomed, 23, pp.81~85 (2007)
- Szegedi A, "Regulatory T cells in atopic dermatitis: epidermal dendritic cell clusters may contribute to their local expansion", Br J Dermatol, 160, pp.984~993 (2009)
- Hanifin JM, "Diagnostic features of atopic dermatitis", Acta Derm Venereol (Stockh 92), (Suppl 92), pp.44~47 (1980)
- Sigmundsdóttir H, "The frequency of CLA+ CD8+ T cells in the blood of psoriasis patients correlates closely with the severity of their disease", Clin Exp Immunol, 126, pp.365~369 (2001)
- Yano S, "Analysis of the expression of cutaneous lymphocyte-associated antigen on the peripheral blood and cutaneous lymphocytes of alopecia areata patients", Acta Derm Venereol, 82, pp.82~85 (2002)
- Santamaria Babi LF, "Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocultured cyte-associated antigen", J Exp Med, 181, pp.1935~1940 (1995)
- Akdis M, "Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells", J Immunol, 159, pp.4611~4619 (1997)
- Leung DY, "Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production", J Exp Med, 181, pp.747~753 (1995)
- Yawalkar N, "Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis", Br J Derma, 144, pp.1133~1139 (2001)
- Pastore S, "The contribution of keratinocytes to the pathogenesis of atopic dermatitis", Eur J Dermatol, 16, pp.125~131 (2006)
- Akdis M, "T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory", effector Th1 cells, 2003, pp.17, 1026~1035
- Hilchey SP, "Use of CFSE to monitor ex vivo regulatory T-cell suppression of CD4+ and CD8+ T-cell proliferation within unseparated mononuclear cells from malignant and non-malignant human lymph node biopsies", Immunol Invest, 36, pp.629~648 (2007)
- Toubi E., "The role of CD4+CD25+ T regulatory cells in autoimmune diseases", Clin Rev Allergy Immunol, 34, pp.338~344 (2008)
- Costantino CM, "Human regulatory T cells and autoimmunity", Eur J Immunol, 38, pp.921~924 (2008)
- Sugiyama H, "Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation", J Immunol, 174, pp.164~173 (2005)
- Antiga E, "Regulatory T cells in skin lesions and blood of patients with bullous pemphigoid", J Eur Acad Dermatol Venereol (2013)
- Lili Y, "Global activation of CD8+ cytotoxic T lymphocytes correlates with an impairment in regulatory T cells in patients with generalized vitiligo", PLoS One, 7, pp.e37513~ (2012)
- Umetsu DT, "Regulatory T cells control the development of allergic disease and asthma", J Allergy Clin Immunol, 112, pp.480~487 (2003)
- Goodman WA, "Regulation generation: the suppressive functions of human regulatory T cells", Crit Rev Immunol, 32, pp.65~79 (2012)
- Nakamura K, "Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta", J Exp Med, 194, pp.629~644 (2001)
