Functional Foxp3+ CD4+ CD25(Bright+) “Natural” Regulatory T Cells Are Abundant in Rabbit Conjunctiva and Suppress Virus-Specific CD4+ and CD8+ Effector T Cells during Ocular Herpes Infection

ABSTRACT We studied the phenotype and distribution of “naturally” occurring CD4+ CD25+ T regulatory cells (CD4+ CD25+ nTreg cells) resident in rabbit conjunctiva, the main T-cell inductive site of the ocular mucosal immune system, and we investigated their suppressive capacities using herpes simplex virus type 1 (HSV-1)-specific effector T (Teff) cells induced during ocular infection. The expression of CD4, CD25, CTLA4, GITR, and Foxp3 was examined by reverse transcription-PCR, Western blotting, and fluorescence-activated cell sorter analysis in CD45+ pan-leukocytes isolated from conjunctiva, spleen, and peripheral blood monocyte cells (PBMC) of HSV-1-infected and uninfected rabbits. Normal conjunctiva showed a higher frequency of CD4+ CD25(Bright+) T cells than did spleen and PBMC. These cells expressed high levels of Foxp3, GITR, and CTLA4 molecules. CD4+ CD25(Bright+) T cells were localized continuously along the upper and lower palpebral and bulbar conjunctiva, throughout the epithelium and substantia propria. Conjunctiva-derived CD4+ CD25(Bright+) T cells, but not CD4+ CD25(low) T cells, efficiently suppressed HSV-specific CD4+ and CD8+ Teff cells. The CD4+ CD25(Bright+) T-cell-mediated suppression was effective on both peripheral blood and conjunctiva infiltrating Teff cells and was cell-cell contact dependent but independent of interleukin-10 and transforming growth factor β. Interestingly, during an ocular herpes infection, there was a selective increase in the frequency and suppressive capacity of Foxp3+ CD4+ CD25(Bright+) T cells in conjunctiva but not in the spleen or in peripheral blood. Altogether, these results provide the first evidence that functional Foxp3+ CD4+ CD25(Bright+) Treg cells accumulate in the conjunctiva. It remains to be determined whether conjunctiva CD4+ CD25+ nTreg cells affect the topical/mucosal delivery of subunit vaccines that stimulate the ocular mucosal immune system.

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Phenotypic and Functional Characterization of Herpes Simplex Virus Glycoprotein B Epitope-Specific Effector and Memory CD8+T Cells from Symptomatic and Asymptomatic Individuals with Ocular Herpes

Journal of Virology ◽

10.1128/jvi.03419-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3776-3792 ◽

Cited By ~ 20

Author(s):

Arif A. Khan ◽

Ruchi Srivastava ◽

Doran Spencer ◽

Sumit Garg ◽

Daniel Fremgen ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Effector Memory ◽

Herpes Infection ◽

Ocular Herpes ◽

Specific Effector ◽

Simplex Virus ◽

Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8+T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8+T cells play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8+T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8+T cells (TEMcells) (CD45RAlowCCR7lowCD44highCD62Llow). In contrast, SYMP patients had frequent less-differentiated central memory CD8+T cells (TCMcells) (CD45RAlowCCR7highCD44lowCD62Lhigh). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8+T cells which responded mainly to gB342–350and gB561–569“ASYMP” epitopes, and simultaneously produced IFN-γ, CD107a/b, granzyme B, and perforin. In contrast, effector CD8+T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17–25and gB183–191“SYMP” epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with “ASYMP” CD8+TEMcell epitopes, but not with “SYMP” CD8+TCMcell epitopes, induced a strong CD8+T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8+TEMcells in protection against herpes and should be considered in the development of an effective vaccine.IMPORTANCEA significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8+T cells (TEMcells) (CD45RAlowCCR7lowCD44highCD62Llow) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8+T cells (TCMcells) (CD45RAlowCCR7highCD44lowCD62Lhigh) in SYMP patients. Immunization with “ASYMP” CD8+TEMcell epitopes, but not with “SYMP” CD8+TCMcell epitopes, induced a strong protective HSV-specific CD8+T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine.

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Abrogation of oral tolerance by contrasuppressor T cells suggests the presence of regulatory T-cell networks in the mucosal immune system

Nature ◽

10.1038/320451a0 ◽

1986 ◽

Vol 320 (6061) ◽

pp. 451-454 ◽

Cited By ~ 49

Author(s):

Iwao Suzuki ◽

Hiroshi Kiyono ◽

Kyoichi Kitamura ◽

Douglas R. Green ◽

Jerry R. McGhee

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Regulatory T Cell ◽

Oral Tolerance ◽

Mucosal Immune System ◽

Cell Networks

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B and T Cell Immunity in Tissues and Across the Ages

Vaccines ◽

10.3390/vaccines9010024 ◽

2021 ◽

Vol 9 (1) ◽

pp. 24

Author(s):

Jayaum S. Booth ◽

Franklin R. Toapanta

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Peripheral Blood ◽

T Cell Immunity ◽

T Cell Subsets ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Cell Immunity ◽

Blood Specimens

B and T cells are key components of the adaptive immune system and coordinate multiple facets of immunity including responses to infection, vaccines, allergens, and the environment. In humans, B- and T-cell immunity has been determined using primarily peripheral blood specimens. Conversely, human tissues have scarcely been studied but they host multiple adaptive immune cells capable of mounting immune responses to pathogens and participate in tissue homeostasis. Mucosal tissues, such as the intestines and respiratory track, are constantly bombarded by foreign antigens and contain tissue-resident memory T (TRM) cells that exhibit superior protective capacity to pathogens. Also, tissue-resident memory B (BRM) cells have been identified in mice but whether humans have a similar population remains to be confirmed. Moreover, the immune system evolves throughout the lifespan of humans and undergoes multiple changes in its immunobiology. Recent studies have shown that age-related changes in tissues are not necessarily reflected in peripheral blood specimens, highlighting the importance of tissue localization and subset delineation as essential determinants of functional B and T cells at different life stages. This review describes our current knowledge of the main B- and T-cell subsets in peripheral blood and tissues across age groups.

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Early Antiretroviral Therapy for Simian Immunodeficiency Virus Infection Leads to Mucosal CD4+ T-Cell Restoration and Enhanced Gene Expression Regulating Mucosal Repair and Regeneration

Journal of Virology ◽

10.1128/jvi.79.5.2709-2719.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 2709-2719 ◽

Cited By ~ 100

Author(s):

Michael D. George ◽

Elizabeth Reay ◽

Sumathi Sankaran ◽

Satya Dandekar

Keyword(s):

Gene Expression ◽

T Cells ◽

Immune System ◽

T Cell ◽

Antiretroviral Therapy ◽

Simian Immunodeficiency Virus ◽

Hiv Infections ◽

Mucosal Immune System ◽

T Cell Subsets ◽

Immunodeficiency Virus

ABSTRACT Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections lead to rapid depletion of CD4+ T cells from gut-associated lymphoid tissue (GALT). Although the administration of antiretroviral therapy (ART) has been shown to increase CD4+ T-cell levels in the peripheral blood in both SIV and HIV infections, its efficacy in restoring intestinal mucosal CD4+ T cells has not been well investigated. To gain insights into the molecular mechanisms of virally induced disruptions in the mucosal immune system, we have evaluated longitudinal changes in viral burden, T-cell subsets, and mucosal gene expression profiles in SIV-infected rhesus macaques in the absence or presence of ART. Our results demonstrate a dramatic suppression of mucosal viral loads and rapid reconstitution of CD4+ T cells in GALT in animals receiving ART that were not observed in untreated SIV-infected animals. DNA microarray-based gene expression profiling indicated that CD4+ T-cell restoration in GALT was associated with up regulation of growth factors and genes involved in repair and regeneration of the mucosal epithelium. In contrast, untreated SIV-infected animals increased expression of lymphocyte activation and inflammatory response-associated genes and did not up regulate mucosal growth and repair associated transcription. In conclusion, these data indicate that initiating ART in primary SIV infection may lead to the restoration of the mucosal immune system through reduction of inflammation and promotion of epithelial repair in the intestinal mucosa.

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Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4+ TEM Cells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Journal of Virology ◽

10.1128/jvi.01991-19 ◽

2020 ◽

Vol 94 (7) ◽

Cited By ~ 1

Author(s):

Ruchi Srivastava ◽

Pierre-Gregoire A. Coulon ◽

Swayam Prakash ◽

Nisha R. Dhanushkodi ◽

Soumyabrata Roy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Effector Memory ◽

Tegument Protein ◽

T Cell Epitopes ◽

Ocular Herpes ◽

Hla Dr ◽

Asymptomatic Individuals ◽

Hsv 1

ABSTRACT While the role of CD8+ T cells in the control of herpes simplex virus 1 (HSV-1) infection and disease is gaining wider acceptance, a direct involvement of effector CD4+ T cells in this protection and the phenotype and function of HSV-specific human CD4+ T cell epitopes remain to be fully elucidated. In the present study, we report that several epitopes from the HSV-1 virion tegument protein (VP11/12) encoded by UL46 are targeted by CD4+ T cells from HSV-seropositive asymptomatic individuals (who, despite being infected, never develop any recurrent herpetic disease). Among these, we identified two immunodominant effector memory CD4+ TEM cell epitopes, amino acids (aa) 129 to 143 of VP11/12 (VP11/12129–143) and VP11/12483–497, using in silico, in vitro, and in vivo approaches based on the following: (i) a combination of the TEPITOPE algorithm and PepScan library scanning of the entire 718 aa of HSV-1 VP11/12 sequence; (ii) an in silico peptide-protein docking analysis and in vitro binding assay that identify epitopes with high affinity to soluble HLA-DRB1 molecules; and (iii) an ELISpot assay and intracellular detection of gamma interferon (IFN-γ), CD107a/b degranulation, and CD4+ T cell carboxyfluorescein succinimidyl ester (CFSE) proliferation assays. We demonstrated that native VP11/12129–143 and VP11/12483–497 epitopes presented by HSV-1-infected HLA-DR-positive target cells were recognized mainly by effector memory CD4+ TEM cells while being less targeted by FOXP3+ CD4+ CD25+ regulatory T cells. Furthermore, immunization of HLA-DR transgenic mice with a mixture of the two immunodominant human VP11/12 CD4+ TEM cell epitopes, but not with cryptic epitopes, induced HSV-specific polyfunctional IFN-γ-producing CD107ab+ CD4+ T cells associated with protective immunity against ocular herpes infection and disease. IMPORTANCE We report that naturally protected HSV-1-seropositive asymptomatic individuals develop a higher frequency of antiviral effector memory CD4+ TEM cells specific to two immunodominant epitopes derived from the HSV-1 tegument protein VP11/12. Immunization of HLA-DR transgenic mice with a mixture of these two immunodominant CD4+ T cell epitopes induced a robust antiviral CD4+ T cell response in the cornea that was associated with protective immunity against ocular herpes. The emerging concept of developing an asymptomatic herpes vaccine that would boost effector memory CD4+ and CD8+ TEM cell responses is discussed.

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Role of CD8+T Cells and Lymphoid Dendritic Cells in Protection from Ocular Herpes Simplex Virus 1 Challenge in Immunized Mice

Journal of Virology ◽

10.1128/jvi.00913-14 ◽

2014 ◽

Vol 88 (14) ◽

pp. 8016-8027 ◽

Cited By ~ 15

Author(s):

Harry Matundan ◽

Kevin R. Mott ◽

Homayon Ghiasi

Keyword(s):

T Cells ◽

T Cell ◽

Vaccine Efficacy ◽

Latent Virus ◽

Ocular Infection ◽

T Cell Exhaustion ◽

Herpes Simplex Virus 1 ◽

Cell Exhaustion ◽

Gm Csf ◽

Hsv 1

ABSTRACTThe development of immunization strategies to protect against ocular infection with herpes simplex virus 1 (HSV-1) must address the issue of the effects of the strategy on the establishment of latency in the trigeminal ganglia (TG). It is the reactivation of this latent virus that can cause recurrent disease and corneal scarring. CD8+T cells and dendritic cells (DCs) have been implicated in the establishment and maintenance of latency through several lines of inquiry. The objective of the current study was to use CD8α−/−and CD8β−/−mice to further evaluate the contributions of CD8+T cells and the CD8α+and CD8α−subpopulations of DCs to the protection afforded against ocular infection by immunization against HSV-1 and their potential to increase latency. Neutralizing antibody titers were similar in immunized CD8α−/−, CD8β−/−, and wild-type (WT) mice, as was virus replication in the eye. However, on day 3 postinfection (p.i.), the copy number of HSV-1 glycoprotein B (gB) was higher in the corneas and TG of CD8α−/−mice than those of WT mice, whereas on day 5 p.i. it was lower. As would be anticipated, the lack of CD8α+or CD8β+cells affected the levels of type I and type II interferon transcripts, but the effects were markedly time dependent and tissue specific. The levels of latent virus in the TG, as estimated by measurement of LAT transcripts andin vitroexplant reactivation assays, were lower in the immunized, ocularly challenged CD8α−/−and WT mice than in their CD8β−/−counterparts. Immunization reduced the expression of PD-1, a marker of T-cell exhaustion, in the TG of ocularly challenged mice, and mock-immunized CD8α−/−mice had lower levels of PD-1 expression and latency than mock-immunized WT or CD8β−/−mice. The expansion of the CD8α−subpopulation of DCs through injection of WT mice with granulocyte-macrophage colony-stimulating factor (GM-CSF) DNA reduced the amount of latency and PD-1 expression in the TG of infected mice. In contrast, injection of FMS-like tyrosine kinase 3 ligand (Flt3L) DNA, which expanded both subpopulations, was less effective. Our results suggest that the absence of both CD8α+T cells and CD8α+DCs does not reduce vaccine efficacy, either directly or indirectly, in challenged mice and that administration of GM-CSF appears to play a beneficial role in reducing latency and T-cell exhaustion.IMPORTANCEIn the past 2 decades, two large clinical HSV vaccine trials were performed, but both vaccine studies failed to reach their goals. Thus, as an alternative to conventional vaccine studies, we have used a different strategy to manipulate the host immune responses in an effort to induce greater protection against HSV infection. In lieu of the pleiotropic effect of CD8α+DCs in HSV-1 latency, in this report, we show that the absence of CD8α+T cells and CD8α+DCs has no adverse effect on vaccine efficacy. In line with our hypothesis, we found that pushing DC subpopulations from CD8α+DCs toward CD8α−DCs by injection of GM-CSF reduced the amount of latent virus and T-cell exhaustion in TG. While these studies point to the lack of a role for CD8α+T cells in vaccine efficacy, they in turn point to a role for GM-CSF in reducing HSV-1 latency.

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Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle

Scientific Reports ◽

10.1038/s41598-021-81474-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Josephine F. Reijneveld ◽

Mira Holzheimer ◽

David C. Young ◽

Kattya Lopez ◽

Sara Suliman ◽

...

Keyword(s):

T Cells ◽

Fatty Acid ◽

Immune System ◽

T Cell ◽

Cross Reactivity ◽

Lipid Binding ◽

Human Immune System ◽

Human T Cell ◽

Human T Cells ◽

Pure Compounds

AbstractThe cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.

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Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution

Genes ◽

10.3390/genes12060813 ◽

2021 ◽

Vol 12 (6) ◽

pp. 813

Author(s):

Norwin Kubick ◽

Pavel Klimovich ◽

Patrick Henckell Flournoy ◽

Irmina Bieńkowska ◽

Marzena Łazarczyk ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Positive Selection ◽

Cd4 T Cells ◽

Cell Function ◽

Single Gene ◽

Ancestral Reconstruction ◽

Critical Function ◽

Interleukin Receptors

Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells’ presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins' emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates' immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system.

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Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Life ◽

10.3390/life11030245 ◽

2021 ◽

Vol 11 (3) ◽

pp. 245

Author(s):

Daniil Shevyrev ◽

Valeriy Tereshchenko ◽

Elena Blinova ◽

Nadezda Knauer ◽

Ekaterina Pashkina ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Autoimmune Diseases ◽

Peripheral Blood ◽

Treg Cells ◽

Homeostatic Proliferation ◽

Suppressive Activity ◽

Healthy Donors

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

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Neonatal lymphocyte subpopulations analysis and maternal preterm premature rupture of membranes: a pilot study

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0375 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Margherita Amadi ◽

Silvia Visentin ◽

Francesca Tosato ◽

Paola Fogar ◽

Giulia Giacomini ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

T Helper Cells ◽

Lymphocyte Subpopulations ◽

T Helper ◽

Premature Rupture Of Membranes ◽

Premature Rupture ◽

Preterm Premature Rupture ◽

Helper Cells

Abstract Objectives Preterm premature rupture of membranes (pPROM) causes preterm delivery, and increases maternal T-cell response against the fetus. Fetal inflammatory response prompts maturation of the newborn’s immunocompetent cells, and could be associated with unfavorable neonatal outcome. The aims were to examine the effects of pPROM (Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstet Gynecol Clin N Am 2005;32:411) on the newborn’s and mother’s immune system and (Test G, Levy A, Wiznitzer A, Mazor M, Holcberg G, Zlotnik A, et al. Factors affecting the latency period in patients with preterm premature rupture of membranes (pPROM). Arch Gynecol Obstet 2011;283:707–10) to assess the predictive value of immune system changes in neonatal morbidity. Methods Mother-newborn pairs (18 mothers and 23 newborns) who experienced pPROM and controls (11 mothers and 14 newborns), were enrolled. Maternal and neonatal whole blood samples underwent flow cytometry to measure lymphocyte subpopulations. Results pPROM-newborns had fewer naïve CD4 T-cells, and more memory CD4 T-cells than control newborns. The effect was the same for increasing pPROM latency times before delivery. Gestational age and birth weight influenced maturation of the newborns’ lymphocyte subpopulations and white blood cells, notably cytotoxic T-cells, regulatory T-cells, T-helper cells (absolute count), and CD4/CD8 ratio. Among morbidities, fewer naïve CD8 T-cells were found in bronchopulmonary dysplasia (BPD) (p=0.0009), and more T-helper cells in early onset sepsis (p=0.04). Conclusions pPROM prompts maturation of the newborn’s T-cell immune system secondary to antigenic stimulation, which correlates with pPROM latency. Maternal immunity to inflammatory conditions is associated with a decrease in non-major histocompatibility complex (MHC)-restricted cytotoxic cells.

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