scholarly journals MR1-Restricted MAIT Cells From The Human Lung Mucosal Surface Have Distinct Phenotypic, Functional, and Transcriptomic Features That Are Preserved in HIV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Sharon Khuzwayo ◽  
Maphe Mthembu ◽  
Erin W. Meermeier ◽  
Sanjay M. Prakadan ◽  
Samuel W. Kazer ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Peripheral Circulation ◽  
Mucosal Surface ◽  
Respiratory Pathogens ◽  
Mait Cells ◽  
And Function ◽  
Mait Cell ◽  
Hiv Negative

Mucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αβ T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of major histocompatibility complex (MHC) class I-related (MR1)-restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in HIV-negative individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with MAIT cell tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in HIV-negative people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.

scholarly journals MR1-restricted MAIT cells from the human lung mucosal surface have distinct phenotypic, functional, and transcriptomic features that are preserved in HIV infection

2020 ◽  
Author(s):  
Sharon Khuzwayo ◽  
Maphe Mthembu ◽  
Erin W. Meermeier ◽  
Sanjay M. Prakadan ◽  
Samuel W. Kazer ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Peripheral Circulation ◽  
Mucosal Surface ◽  
Respiratory Pathogens ◽  
Healthy Individuals ◽  
Mait Cells ◽  
And Function ◽  
Mait Cell

AbstractMucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αβ T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of MR1 restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in healthy individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with atypical MAIT cells and tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in healthy people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.

scholarly journals Direct Evidence for Thymic Function in Adult Humans

1999 ◽  
Vol 190 (4) ◽  
pp. 479-486 ◽  
Author(s):  
Jean-François Poulin ◽  
Mohan N. Viswanathan ◽  
Jeffrey M. Harris ◽  
Krishna V. Komanduri ◽  
Eric Wieder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Peripheral Circulation ◽  
Older Individuals ◽  
T Cell Homeostasis ◽  
Thymic Function ◽  
Adult Thymus ◽  
Adult Peripheral Blood

The understanding of human thymic function and evaluation of its contribution to T cell homeostasis are matters of great importance. Here we report the development of a novel assay to quantitate the frequency and diversity of recent thymic emigrants (RTEs) in the peripheral blood of humans. Such cells were defined by the presence of T cell receptor (TCR) rearrangement deletion circles (DCs), episomal byproducts of TCR-β V(D)J rearrangement. DCs were detected in T cells in the thymus, cord blood, and adult peripheral blood. In the peripheral blood of adults aged 22 to 76 years, their frequency was highest in the CD4+CD45RA+ CD62L+ subpopulation of naive T cells. TCR DCs were also observed in other subpopulations of peripheral blood T cells, including those with the CD4+CD45RO−CD62L+ and CD4+CD45RO+CD62L+ phenotypes. RTEs were observed to have more than one Vβ rearrangement, suggesting that replenishment of the repertoire in the adult is at least oligoclonal. These results demonstrate that the normal adult thymus continues to contribute, even in older individuals, a diverse set of new T cells to the peripheral circulation.

scholarly journals The Frequency of BDCA3-Positive Dendritic Cells Is Increased in the Peripheral Circulation of Kenyan Children with Severe Malaria

2006 ◽  
Vol 74 (12) ◽  
pp. 6700-6706 ◽  
Author(s):  
Britta C. Urban ◽  
Damien Cordery ◽  
Mohammed J. Shafi ◽  
Peter C. Bull ◽  
Christopher I. Newbold ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Severe Malaria ◽  
Peripheral Blood ◽  
Plasma Concentrations ◽  
Peripheral Circulation ◽  
Interleukin 10 ◽  
Low Concentrations ◽  
High Concentrations ◽  
And Function ◽  
Antigen Presenting

ABSTRACT The ability of Plasmodium falciparum-infected erythrocytes to adhere to host endothelial cells via receptor molecules such as ICAM-1 and CD36 is considered a hallmark for the development of severe malaria syndromes. These molecules are also expressed on leukocytes such as dendritic cells. Dendritic cells are antigen-presenting cells that are crucial for the initiation of adaptive immune responses. In many human diseases, their frequency and function is perturbed. We analyzed the frequency of peripheral blood dendritic cell subsets and the plasma concentrations of interleukin-10 (IL-10) and IL-12 in Kenyan children with severe malaria and during convalescence and related these parameters to the adhesion phenotype of the acute parasite isolates. The frequency of CD1c+ dendritic cells in children with acute malaria was comparable to that in healthy controls, but the frequency of BDCA3+ dendritic cells was significantly increased. Analysis of the adhesion phenotypes of parasite isolates revealed that adhesion to ICAM-1 was associated with the frequency of peripheral blood CD1c+ dendritic cells, whereas the adhesion of infected erythrocytes to CD36 correlated with high concentrations of IL-10 and low concentrations of IL-12 in plasma.

scholarly journals Influenza A Virus Infection v1

2020 ◽  
Author(s):  
Timothy S C Hinks ◽  
Bonnie van Wilgenburg ◽  
Huimeng Wang ◽  
Liyen Loh ◽  
Marios Koutsakos ◽  
...  
Keyword(s):  
Influenza A ◽  
Cell Activation ◽  
Viral Infections ◽  
Intracellular Cytokine Staining ◽  
Cell Receptor ◽  
Type I ◽  
Independent Manner ◽  
Mait Cells ◽  
Mait Cell

This is part 3.3 of the "Study of MAIT Cell Activation in Viral Infections In Vivo" collection of protocols. Collection Abstract: MAIT cells are abundant, highly evolutionarily conserved innate-like lymphocytes expressing a semi-invariant T cell receptor (TCR), which recognizes microbially derived small intermediate molecules from the riboflavin biosynthetic pathway. However, in addition to their TCR-mediated functions they can also be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon. Emerging data suggest that they are expanded and activated by a range of viral infections, and significantly that they can contribute to a protective anti-viral response. Here we describe methods used to investigate these anti-viral functions in vivo in murine models. To overcome the technical challenge that MAIT cells are rare in specific pathogen-free laboratory mice, we describe how pulmonary MAIT cells can be expanded using intranasal bacterial infection or a combination of synthetic MAIT cell antigen and TLR agonists. We also describe protocols for adoptive transfer of MAIT cells, methods for lung homogenization for plaque assays, and surface and intracellular cytokine staining to determine MAIT cell activation.

scholarly journals MAIT cells are minimally responsive to Mycobacterium tuberculosis within granulomas, but are functionally impaired by SIV in a macaque model of SIV and Mtb co-infection

2020 ◽  
Author(s):  
Amy L. Ellis-Connell ◽  
Alexis J. Balgeman ◽  
Erica C. Larson ◽  
Mark A. Rodgers ◽  
Cassaundra Ameel ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cell Activation ◽  
Cell Function ◽  
Ex Vivo ◽  
Cynomolgus Macaque ◽  
Cross Sectional ◽  
In Vivo Models ◽  
Mait Cells ◽  
Mait Cell

ABSTRACTMucosal associated invariant T (MAIT) cells recognize and can directly destroy bacterially infected cells. While a role for MAIT cells has been suggested in several in vitro and in vivo models of M.tuberculosis (Mtb) infection, these studies have often focused on MAIT cells within the peripheral blood or are cross-sectional studies rather than longitudinal studies. The role of MAIT cells within granulomas and other sites of Mtb infection is relatively unknown. Furthermore, how HIV/SIV infection might impair MAIT cells at the sites of Mtb infection has not been determined. Using a Mauritian cynomolgus macaque (MCM) model system, we phenotyped MAIT cells in the peripheral blood and BAL prior to and during infection with SIVmac239. To characterize the role of MAIT cells within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb for 6 weeks. MAIT cell frequency and function was examined within the peripheral blood, distal airways, as well as within Mtb-affected lymph nodes (LN) and tissues. Surprisingly, we found no evidence of MAIT cell responsiveness to Mtb within granulomas. Additionally, MAIT cells only minimally responded to mycobacterial stimulus in ex vivo functional assays. In contrast, most MAIT cell activation seemed to occur in samples with highly active SIV replication, including blood and SIV-infected LN. Finally, the ability of MAIT cells to secrete TNFα (TNF) was impaired during SIV and Mtb co-infection, indicating that the two pathogens together could have a synergistically deleterious effect on MAIT cell function. The effect of this functional impairment on overall TB disease burden was unclear, but might be deleterious if MAIT cells are needed to fully activate antimycobacterial immune cells within the granulomas.

scholarly journals MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Tingting Liu ◽  
Jie Wang ◽  
Kalpana Subedi ◽  
Qijun Yi ◽  
Li Zhou ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
Loss Of Function ◽  
Mait Cells ◽  
Cellular Processes ◽  
Individual Mirnas ◽  
Maturation Stages ◽  
And Function ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

Factors influencing tymic function in 55 patients with lymphomas: Candidates to autologous stem cell transplantation (ASCT)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18512-18512 ◽  
Author(s):  
C. Simonelli ◽  
C. Pratesi ◽  
S. Zanussi ◽  
R. Talamini ◽  
M. Rupolo ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
De Novo ◽  
Good Control ◽  
Cell Receptor ◽  
Hiv Positive ◽  
First Line ◽  
Hiv Replication ◽  
Excision Circles ◽  
Hiv Negative

18512 Background: Signal joint T cell receptor excision circles (sjTRECs) have been reported to be a clinical marker to evaluate the tymic reservoir after immunosuppression treatments. Methods: We studied the sjTRECs levels in a mono-institutional series of a cohort of 26 HIV-positive and 29 HIV-negative pts with relapsed or refractory lymphomas, candidates to ASCT, considering important biological and clinical characteristics, virological parameters and immunological settings including age, type of lymphoma, number of first line CT cycles, time from the end of first line chemotherapy to the enrolment (TECT), HIV infection and T subpopulations. Results: The overall study subjects, showed lower sjTRECs levels than healthy donors (p<0.01), but no differences in the sjTRECs content were seen between HIV-negative and HIV-positive pts (536 vs. 401 TRECs/106 PBMCs, respectively) as well as in the T cell naive count. We found a significant correlation between the sjTRECs decay and the increase of age (r=-0.32, p=0.02), CD4 and CD8 naive cell count and the sjTRECs level; on the contrary we did not observe any significant correlation between CT cycles number TECT, lymphoma type in both subgroups. HIV-positive viremic pts showed significant lower level of sjTRECs level than averimic pts. Conclusions: Our analyses suggest that de novo T cell generation is partially maintained in lymphoma pts’ candidates to ASCT and could contribute to restore the immune function after transplantation. Chemotherapeutic treatments seem to induce a similar influence on thymic output despite their intensity and, surprisingly, HIV infection is not a detrimental factor on thymic reservoir at the time of lymphoma relapse, and a good control of HIV replication seems to preserve thymic reservoir. No significant financial relationships to disclose.

scholarly journals MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lauren J. Howson ◽  
Giorgio Napolitani ◽  
Dawn Shepherd ◽  
Hemza Ghadbane ◽  
Prathiba Kurupati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Receptor ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Mait Cells ◽  
Vaccination Strategies ◽  
Human Volunteers ◽  
Tcr Repertoire ◽  
Cell Clonal Expansion ◽  
Mait Cell

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.

scholarly journals The CD4−CD8− MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8+ MAIT cell pool

2018 ◽  
Vol 115 (49) ◽  
pp. E11513-E11522 ◽  
Author(s):  
Joana Dias ◽  
Caroline Boulouis ◽  
Jean-Baptiste Gorin ◽  
Robin H. G. A. van den Biggelaar ◽  
Kerri G. Lal ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Gene Signature ◽  
Cell Subpopulation ◽  
Bacterial Strains ◽  
Mait Cells ◽  
Receptor Repertoire ◽  
Mait Cell

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells predominantly express the CD8α coreceptor (CD8+), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8α represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8+ MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher RORγt/T-bet ratio, and express less IFN-γ and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8+ subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8+ MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8+ MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8+ and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship.

scholarly journals Mucosal-Associated Invariant T (MAIT) Cells are Highly Activated in Duodenal Tissue of Humans with Vibrio cholerae O1 Infection

2021 ◽  
Author(s):  
Taufiqur Bhuiyan ◽  
M. Arifur Rahman ◽  
Shubhanshi Trivedi ◽  
Taliman Afroz ◽  
Hassan Al Banna ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Lamina Propria ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Acute Stage ◽  
Mhc I ◽  
Mait Cells ◽  
Intestinal Infections ◽  
Vibrio Cholerae O1 ◽  
Duodenal Biopsies

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes with a semi-conserved TCR-alpha, activated by the presentation of vitamin B metabolites by the MHC-I related protein, MR1, and with diverse innate and adaptive effector functions. The role of MAIT cells in acute intestinal infections, especially at the mucosal level, is not well known. Here, we analyzed the presence and phenotype of MAIT cells in duodenal biopsies and paired peripheral blood samples, in patients during and after culture-confirmed Vibrio cholerae O1 infection. Immunohistochemical staining of duodenal biopsies from cholera patients identified MAIT cells in the lamina propria, but not in the lining of villous and crypt epithelia. We observed significantly higher frequencies of duodenal MAIT cells at the acute stage (day 2) of V. cholerae infection as compared to late convalescence (day 30, p = 0.0049). By flow cytometry, we showed that duodenal MAIT cells are more activated than peripheral MAIT cells (p < 0.01 across time points), although there were no significant differences between duodenal MAITs at day 2 and day 30. We found fecal markers of intestinal permeability and inflammation to be correlated with the loss of duodenal (but not peripheral) MAIT cells, and single-cell sequencing revealed differing T cell receptor usage between the duodenal and peripheral blood MAIT cells. In summary, we show that MAIT cells are present and highly activated in the lamina propria of the duodenum during V. cholerae infection. Future work into the trafficking and tissue-resident function of MAIT cells is warranted.

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