Impaired CD8(+) T cell responses upon Toll-like receptor activation in common variable immunodeficiency
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Citações na Scopus
14
Tipo de produção
article
Data de publicação
2016
Título da Revista
ISSN da Revista
Título do Volume
Editora
BIOMED CENTRAL LTD
Citação
JOURNAL OF TRANSLATIONAL MEDICINE, v.14, article ID 138, 11p, 2016
Resumo
Background: Infections caused by bacteria or viruses are frequent in common variable immunodeficiency (CVID) patients due to antibody deficiencies, which may be associated with altered T cell function. CVID patients are frequently in contact with pathogen-associated molecular patterns (PAMPs), leading to the activation of innate immunity through Toll-like receptors (TLR) affecting T cell activation. We evaluated the effect of TLR activation on T cells in CVID patients undergoing intravenous immunoglobulin (IVIg) replacement using synthetic ligands. Methods: Expression of exhaustion, activation and maturation markers on T cells from peripheral blood as well as regulatory T cells and follicular T cells in peripheral blood mononuclear cells (PBMCs) from CVID and healthy individuals were evaluated by flow cytometry. PBMCs cultured with TLR agonists were assessed for intracellular IFN-gamma, TNF, IL-10, IL-17a or IL-22 secretion as monofunctional or polyfunctional T cells (simultaneous cytokine secretion) by flow cytometry. Results: We found increased expression of the exhaustion marker PD-1 on effector memory CD4(+) T cells (CD45RA(-)CCR7(-)) in the peripheral blood and increased expression of CD38 in terminally differentiated CD8(+) T cells (CD45RA(+)CCR7(-)). Furthermore, a decreased frequency of naive regulatory T cells (CD45RA(+)Foxp3(low)), but not of activated regulatory T cells (CD45RA(-)Foxp3(high)) was detected in CVID patients with splenomegaly, the noninfectious manifestation in this CVID cohort (43.7 %). Moreover, the frequency of peripheral blood follicular helper T cells (CD3(+)CD4(+)CXCR5(+)PD-1(+)ICOS(+)) was similar between the CVID and control groups. Upon in vitro TLR3 activation, a decreased frequency of CD8(+) T cells secreting IFN-gamma, IL-17a or IL-22 was detected in the CVID group compared to the control group. However, a TLR7/TLR8 agonist and staphylococcal enterotoxin B induced an increased Th22/Tc22 (IL-22(+), IFN-gamma(-), IL-17a(-)) response in CVID patients. Both TLR2 and TLR7/8/CL097 activation induced an increased response of CD4(+) T cells secreting three cytokines (IL-17a, IL-22 and TNF) in CVID patients, whereas CD8(+) T cells were unresponsive to these stimuli. Conclusion: The data show that despite the unresponsive profile of CD8(+) T cells to TLR activation, CD4(+) T cells and Tc22/Th22 cells are responsive, suggesting that activation of innate immunity by TLRs could be a strategy to stimulate CD4(+) T cells in CVID.
Palavras-chave
Common variable immunodeficiency, Exhaustion and activation markers, Toll-like receptor agonists, Tc22/Th22, Polyfunctional T cells
Referências
- Zarember KA, 2002, J IMMUNOL, V168, P554
- Miyara M, 2009, IMMUNITY, V30, P899, DOI 10.1016/j.immuni.2009.03.019
- Maglione PJ, 2015, ANN NY ACAD SCI, V1356, P1, DOI 10.1111/nyas.12763
- Trifari S, 2009, NAT IMMUNOL, V10, P864, DOI 10.1038/ni.1770
- Hervas-Stubbs S, 2007, BLOOD, V109, P5318, DOI 10.1182/blood-2006-10-053256
- Warnatz K, 2002, IMMUNOBIOLOGY, V206, P502, DOI 10.1078/0171-2985-00198
- Macian F, 2002, CELL, V109, P719, DOI 10.1016/S0092-8674(02)00767-5
- Genre J, 2009, CLIN IMMUNOL, V132, P215, DOI 10.1016/j.clim.2009.03.519
- Chapel H, 2009, BRIT J HAEMATOL, V145, P709, DOI 10.1111/j.1365-2141.2009.07669.x
- Dropulic LK, 2011, CLIN INFECT DIS, V53, P897, DOI 10.1093/cid/cir610
- Gathmann B, 2014, J ALLERGY CLIN IMMUN, V134, P116, DOI 10.1016/j.jaci.2013.12.1077
- Josefowicz SZ, 2012, ANNU REV IMMUNOL, V30, P531, DOI 10.1146/annurev.immunol.25.022106.141623
- Giovannetti A, 2007, J IMMUNOL, V178, P3932
- Caron G, 2005, J IMMUNOL, V175, P1551
- Kawai T, 2010, NAT IMMUNOL, V11, P373, DOI 10.1038/ni.1863
- Domingues R, 2015, BRIT J DERMATOL, V172, P48, DOI 10.1111/bjd.13214
- Kulkarni R, 2011, CELL TISSUE RES, V343, P141, DOI 10.1007/s00441-010-1017-1
- Kim CJ, 2012, MUCOSAL IMMUNOL, V5, P670, DOI 10.1038/mi.2012.72
- Komai-Koma M, 2004, P NATL ACAD SCI USA, V101, P3029, DOI 10.1073/pnas.0400171101
- Sonnenberg GF, 2011, NAT IMMUNOL, V12, P383, DOI 10.1038/ni.2025
- Duhen T, 2009, NAT IMMUNOL, V10, P857, DOI 10.1038/ni.1767
- Conley ME, 1999, CLIN IMMUNOL, V93, P190, DOI 10.1006/clim.1999.4799
- Arumugakani G, 2010, J CLIN IMMUNOL, V30, P292, DOI 10.1007/s10875-009-9351-3
- Salem ML, 2011, IMMUNOL LETT, V137, P9, DOI 10.1016/j.imlet.2011.02.019
- De Luca A, 2010, MUCOSAL IMMUNOL, V3, P361, DOI 10.1038/mi.2010.22
- Bateman EAL, 2012, CLIN EXP IMMUNOL, V170, P202, DOI 10.1111/j.1365-2249.2012.04643.x
- Reynolds JM, 2010, IMMUNITY, V32, P692, DOI 10.1016/j.immuni.2010.04.010
- Cunningham-Rundles C, 1999, CLIN IMMUNOL, V92, P34, DOI 10.1006/clim.1999.4725
- Cardoso EC, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0067036
- Cunningham-Rundles C, 2010, BLOOD, V116, P7, DOI 10.1182/blood-2010-01-254417
- Hel Z, 2014, J CLIN IMMUNOL, V34, P971, DOI 10.1007/s10875-014-0099-z
- MacLeod Heather, 2007, Sci STKE, V2007, ppe48, DOI 10.1126/stke.4022007pe48
- Pan XJ, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0034662
- Paquin-Proulx D, 2014, FRONT IMMUNOL, V5, DOI 10.3389/fimmu.2014.00637
- Paquin-Proulx D, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0075199
- Perreau M, 2014, J EXP MED, V211, P2033, DOI 10.1084/jem.20140039
- Yu JE, 2009, J ALLERGY CLIN IMMUN, V124, P349, DOI 10.1016/j.jaci.2009.05.019
Coleções
Artigos e Materiais de Revistas Científicas - FM/MPE
Artigos e Materiais de Revistas Científicas - FM/MDT
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - HC/ICr
Artigos e Materiais de Revistas Científicas - LIM/36
Carregar mais Artigos e Materiais de Revistas Científicas - FM/MDT
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - HC/ICr
Artigos e Materiais de Revistas Científicas - LIM/36