Generation and Regulation of CD8+ Regulatory T Cells

Lu, Linrong; Cantor, Harvey

doi:10.1038/cmi.2008.50

Cited by 88 publications

(63 citation statements)

References 42 publications

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Section: Discussionmentioning

confidence: 74%

“…tuberculosis peptide specific CD8 T cells more closely resemble Tc2 T cells and accordingly they are capable to provide help to B lymphocytes for Ab production. Moreover, the finding that some CD8 T-cell lines also secrete TGF-β suggests that a fraction of these cells might play regulatory activities, as shown by previous studies in autoimmune disease models [46] and response to microorganisms [47], including TB [13].Overall, data reported here differ from previously described HLA-E-restricted, TB-specific CD8 T cells that produce IFN-γ and are cytolytic [12,13]. However, we would like to point that in the Heinzel paper [12] only two HLA-E-restricted and TB-specific CD8 T-cell clones were studied, both derived from one healthy LTBI subject, and cytotoxic activity of the clones was not assessed.…”

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confidence: 62%

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Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA‐E during active tuberculosis and express type 2 cytokines

et al. 2015

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CD8 T cells contribute to protective immunity against Mycobacterium tuberculosis. In humans, M. tuberculosis reactive CD8 T cells typically recognize peptides associated to classical MHC class Ia molecules, but little information is available on CD8 T cells recognizing M. tuberculosis Ags presented by nonclassical MHC class Ib molecules.We show here that CD8 T cells from tuberculosis (TB) patients recognize HLA-E-binding M. tuberculosis peptides in a CD3/TCR αβ mediated and CD8-dependent manner, and represent an additional type of effector cells playing a role in immune response to M. tuberculosis during active infection. HLA-E-restricted recognition of M. tuberculosis peptides is detectable by a significant enhanced ex vivo frequency of tetramer-specific circulating CD8 T cells during active TB. These CD8 T cells produce type 2 cytokines upon antigenic in vitro stimulation, help B cells for Ab production, and mediate limited TRAIL-dependent cytolytic and microbicidal activity toward M. tuberculosis infected target cells. Our results, together with the finding that HLA-E/M. tuberculosis peptide specific CD8 T cells are detected in TB patients with or without HIV coinfection, suggest that this is a new human T-cell population that participates in immune response in TB.Keywords: CD8 T lymphocytes r HLA-E r Mycobacterium tuberculosis r TB r Tetramers r Type 2 cytokines Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Francesco Dieli e-mail: francesco.dieli@unipa.it * These authors share first authorship for this work.* * These authors share last authorship for this work. [2]. In humans, M. tuberculosis reactive CD8 T cells recognize peptides associated to classical HLA-A, HLA-B, and HLA-C class I (class Ia) molecules, glycolipids associated to group 1 CD1 molecules [5,6], and mycobacterial Ag associated to MHC class I related molecule (MR1) [7]. However, there is little information on the role that these cells play during infection. In mice, the MHC class Ib molecule H2-M3 binds formylated peptides derived from M. tuberculosis and induces H2-M3-restricted CD8 T cells [8,9] that are protective against M. tuberculosis infection [10]. In humans, CD8 T cells restricted by class Ib molecules comprise the very large majority of the overall M. tuberculosis specific CD8 T-cell response [11] and CD8 T cells recognizing M. tuberculosis Ags in the context of the class Ib molecule HLA-E have been isolated from subjects with latent M. tuberculosis infection [12,13]. However, the functions of this HLA-E-restricted population, as well as its contribution to the host response to M. tuberculosis during infection and disease, remain unknown.HLA-E is the least polymorphic of all the HLA molecules [14] with only two alleles in the Caucasian population, which differ at one aa position located outside the peptidebinding groove [15]. Physiologically, HLA-E binds nonamer peptides derived from the signal sequence of other HLA class I molecules [16,17], a...

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Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 62%

Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA‐E during active tuberculosis and express type 2 cytokines

et al. 2015

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“…CD8 + Treg cells' involvement in maintaining self-tolerance was recently identified (8,9). These cells' surface markers include CD25, CD103, and CD122 (10,11). CD8 + Treg cells with regulatory function express transcription factor Foxp3 (11)(12)(13).…”

Section: Cd25mentioning

confidence: 99%

“…These cells' surface markers include CD25, CD103, and CD122 (10,11). CD8 + Treg cells with regulatory function express transcription factor Foxp3 (11)(12)(13). Human CD8 + Treg cells are implicated in various infectious diseases (14-16) and autoimmune disorders, including multiple sclerosis (17) and inflammatory bowel disease (18) Allergen-specific immunotherapy (IT) by repeated s.c. administration of increased doses of allergen extracts has a long-lasting effect on immune tolerance to common environmental allergens (25)(26)(27).…”

Section: Cd25mentioning

confidence: 99%

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Tsai

Yang

Niu

et al. 2010

The Journal of Immunology

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Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8+CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies.

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“…[32][33][34] We described the important role of TCV in limiting autoimmune nephritis induced by Fx1A immunization. Rats were protected from renal injury by TCV, with normal renal function and significantly reduced proteinuria and autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

CD8+ Regulatory T Cells Induced by T Cell Vaccination Protect Against Autoimmune Nephritis

Wang

Zhang

et al. 2012

Journal of the American Society of Nephrology

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Autoreactive T cells play a pivotal role in the pathogenesis of autoimmune kidney disease. T cell vaccination (TCV) may limit autoimmune disease and induce CD8+ regulatory T cells (Tregs). We used Heymann nephritis (HN), a rat model of human membranous nephritis, to study the effects of TCV on autoimmune kidney disease. We harvested CD4+ T cells from renal tubular antigen (Fx1A) -immunized rats and activated these cells in vitro to express the MHC Class Ib molecule Qa-1. Vaccination of Lewis rats with these autoreactive Fx1A-induced T cells protected against HN, whereas control-primed T cells did not. Rats that underwent TCV had lower levels of proteinuria and serum creatinine and significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates. Furthermore, these rats expressed less IFN-g and IL-6 in splenocytes, whereas the numbers of Tregs and the expression of Foxp3 were unchanged. In vitro cytotoxicity assays showed CD8+ T cell-mediated elimination of Qa-1-expressing CD4+ T cells. In vivo, TCV abrogated the increase in Qa-1-expressing CXCR5+ TFH cells observed in HN compared with controls. Taken together, these results suggest that TCV protects against autoimmune kidney disease by targeting Qa-1-expressing autoreactive CD4+ cells.

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Generation and Regulation of CD8+ Regulatory T Cells

Cited by 88 publications

References 42 publications

Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA‐E during active tuberculosis and express type 2 cytokines

Human CD8 T lymphocytes recognize Mycobacterium tuberculosis antigens presented by HLA‐E during active tuberculosis and express type 2 cytokines

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

CD8+ Regulatory T Cells Induced by T Cell Vaccination Protect Against Autoimmune Nephritis

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