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Impaired CD8(+) T cell responses upon Toll-like receptor activation in common variable immunodeficiency.
J Transl Med 2016; 14(1):138JT

Abstract

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-γ, 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 naïve regulatory T cells (CD45RA(+)Foxp3(low)), but not of activated regulatory T cells (CD45RA(-)Foxp3(high)) was detected in CVID patients with splenomegaly, the non-infectious 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-γ, 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-γ(-), 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.

Authors+Show Affiliations

Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, Medical School, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 500, 3rd Floor, São Paulo, 05403-000, Brazil.Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, Medical School, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 500, 3rd Floor, São Paulo, 05403-000, Brazil.Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, Medical School, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 500, 3rd Floor, São Paulo, 05403-000, Brazil.Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, Medical School, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 500, 3rd Floor, São Paulo, 05403-000, Brazil.Department of Pediatrics, Medical School, University of São Paulo, São Paulo, Brazil.Department of Pediatrics, Medical School, University of São Paulo, São Paulo, Brazil.Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, Medical School, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 500, 3rd Floor, São Paulo, 05403-000, Brazil.Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology, Medical School, Tropical Medicine Institute, University of São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 500, 3rd Floor, São Paulo, 05403-000, Brazil. marisato@usp.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27188997

Citation

de Lollo, Camila, et al. "Impaired CD8(+) T Cell Responses Upon Toll-like Receptor Activation in Common Variable Immunodeficiency." Journal of Translational Medicine, vol. 14, no. 1, 2016, p. 138.
de Lollo C, de Moraes Vasconcelos D, da Silva Oliveira LM, et al. Impaired CD8(+) T cell responses upon Toll-like receptor activation in common variable immunodeficiency. J Transl Med. 2016;14(1):138.
de Lollo, C., de Moraes Vasconcelos, D., da Silva Oliveira, L. M., de Oliveira Titz, T., Carneiro-Sampaio, M., Jacob, C. M., ... Sato, M. N. (2016). Impaired CD8(+) T cell responses upon Toll-like receptor activation in common variable immunodeficiency. Journal of Translational Medicine, 14(1), p. 138. doi:10.1186/s12967-016-0900-2.
de Lollo C, et al. Impaired CD8(+) T Cell Responses Upon Toll-like Receptor Activation in Common Variable Immunodeficiency. J Transl Med. 2016 05 17;14(1):138. PubMed PMID: 27188997.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired CD8(+) T cell responses upon Toll-like receptor activation in common variable immunodeficiency. AU - de Lollo,Camila, AU - de Moraes Vasconcelos,Dewton, AU - da Silva Oliveira,Luanda Mara, AU - de Oliveira Titz,Tiago, AU - Carneiro-Sampaio,Magda, AU - Jacob,Cristina Miuki Abe, AU - da Silva Duarte,Alberto José, AU - Sato,Maria Notomi, Y1 - 2016/05/17/ PY - 2015/12/30/received PY - 2016/05/07/accepted PY - 2016/5/19/entrez PY - 2016/5/18/pubmed PY - 2017/10/17/medline KW - Common variable immunodeficiency KW - Exhaustion and activation markers KW - Polyfunctional T cells KW - Tc22/Th22 KW - Toll-like receptor agonists SP - 138 EP - 138 JF - Journal of translational medicine JO - J Transl Med VL - 14 IS - 1 N2 - 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-γ, 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 naïve regulatory T cells (CD45RA(+)Foxp3(low)), but not of activated regulatory T cells (CD45RA(-)Foxp3(high)) was detected in CVID patients with splenomegaly, the non-infectious 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-γ, 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-γ(-), 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. SN - 1479-5876 UR - https://www.unboundmedicine.com/medline/citation/27188997/Impaired_CD8_+__T_cell_responses_upon_Toll_like_receptor_activation_in_common_variable_immunodeficiency_ L2 - https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0900-2 DB - PRIME DP - Unbound Medicine ER -