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The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity.

Napier RJ, Adams EJ, Gold MC, Lewinsohn DM - Front Immunol (2015)

Bottom Line: Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and distributed throughout the blood and mucosal sites.Studies performed in MR1-deficient mice suggest that MAIT cells can provide anti-bacterial control within the first few days post-infection, as well as contribute to enhanced adaptive immunity in murine models of respiratory infections.Given that MAIT cells are pro-inflammatory, serve in early control of bacterial infections, and appear enriched at tissue sites where microbes interface and gain access to the body, we postulate that they play an important role in antimicrobial immune responses.

View Article: PubMed Central - PubMed

Affiliation: Pulmonary and Critical Care Medicine, Oregon Health & Science University , Portland, OR , USA.

ABSTRACT
Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and distributed throughout the blood and mucosal sites. Human MAIT cells are defined by the expression of the semi-invariant TCRα chain TRAV1-2/TRAJ12/20/33 and are restricted by the non-polymorphic major histocompatibility complex (MHC) class I-like molecule, MHC-related protein 1, MR1. MAIT cells are activated by small organic molecules, derived from the riboflavin biosynthesis pathway of bacteria and fungi, presented by MR1. Traditionally, MAIT cells were thought to recognize a limited number of antigens due to usage of an invariant TCRα chain and restriction by a non-polymorphic MHC molecule. However, recent studies demonstrate that the TCR repertoire of MAIT cells is more heterogeneous, suggesting there is a more diverse array of MR1 antigens that MAIT cells can recognize. In response to infected cells, MAIT cells produce the pro-inflammatory cytokines, IFN-γ and TNF, and are cytolytic. Studies performed in MR1-deficient mice suggest that MAIT cells can provide anti-bacterial control within the first few days post-infection, as well as contribute to enhanced adaptive immunity in murine models of respiratory infections. In humans, the role of MAIT cells is unclear; however, evidence points to interplay between MAIT cells and microbial infections, including Mycobacterium tuberculosis. Given that MAIT cells are pro-inflammatory, serve in early control of bacterial infections, and appear enriched at tissue sites where microbes interface and gain access to the body, we postulate that they play an important role in antimicrobial immune responses. In this review, we discuss the most recent studies on the function and phenotype of MAIT cells, including their TCR diversity and antigenic repertoire, with a focus on the contribution of human MAIT cells in the immune response to microbial infection.

No MeSH data available.


Related in: MedlinePlus

Molecular basis of antigen presentation by MR1 and recognition by MAIT TCRs. (A) Backbone (ribbon) and surface representations of the structure of human MR1 (PDB ID: 4GUP) are shown in cyan. In the MR1, A′ pocket is shown the 6-FP ligand in yellow, with nitrogen atoms colored blue, and oxygen in red. The A′ and F′ pockets are labeled as such. (B) MAIT TCR recognition of MR1 presenting the stimulatory antigen, rRL (rRL-6-CH2OH) (PDB ID: 4LCC), only CDR loops of the MAIT TCR are shown, positioned in complex with MR1. CDRa loops are colored pink; CDRb are shown in blue. The rRL antigen is shown as above for 6-FP. In the insert is a zoomed view of the CDR3a (Y95) and CDR3b (E99) loop interactions with the ribtyl chain of rRL, showing the hydrogen-bonds as yellow dashes.
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Figure 1: Molecular basis of antigen presentation by MR1 and recognition by MAIT TCRs. (A) Backbone (ribbon) and surface representations of the structure of human MR1 (PDB ID: 4GUP) are shown in cyan. In the MR1, A′ pocket is shown the 6-FP ligand in yellow, with nitrogen atoms colored blue, and oxygen in red. The A′ and F′ pockets are labeled as such. (B) MAIT TCR recognition of MR1 presenting the stimulatory antigen, rRL (rRL-6-CH2OH) (PDB ID: 4LCC), only CDR loops of the MAIT TCR are shown, positioned in complex with MR1. CDRa loops are colored pink; CDRb are shown in blue. The rRL antigen is shown as above for 6-FP. In the insert is a zoomed view of the CDR3a (Y95) and CDR3b (E99) loop interactions with the ribtyl chain of rRL, showing the hydrogen-bonds as yellow dashes.

Mentions: The structural elucidation of MR1 provided the first insight into the nature of ligands presented by this molecule (6, 32). The overall backbone structure of MR1 is most closely related to the classical class I MHC, HLA-A2; however, the antigen-presenting groove has a number of unique features. The MR1 cavity is smaller and has two pocket structures capable of binding small molecule antigens (Figure 1A). The A′ pocket, named as such due to the similarity in location to the A′ tunnels in CD1 molecules, is lined with aromatic and basic residues, creating a small, positively charged cavity that is almost entirely sequestered from external solvent. An additional pocket, termed F′ (similar in location to the F′ tunnel in CD1 molecules), is more shallow and can be variable in size due to flexibility noted in the structure of the α2 helix of human MR1(6). A comparison between the two molecules in the asymmetric unit of the human structure revealed an ~11Å shift between the positioning of the N-terminal portion of the α2 helix, with one molecule having a significantly inward-shifted helix resulting in a pseudo-collapsed F′ pocket. The structure of the A′ pocket was almost identical between the two structures, suggesting that this flexibility would not directly affect antigens presented in this pocket, although this phenomenon may shed light onto the molecular mechanisms of ligand loading. Curiously, this conformational flexibility was not apparent in the structure of bovine MR1 solved in complex with a MAIT TCR; either bovine MR1 has greater rigidity in this region or complexation with a TCR stabilizes this region of MR1(32).


The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity.

Napier RJ, Adams EJ, Gold MC, Lewinsohn DM - Front Immunol (2015)

Molecular basis of antigen presentation by MR1 and recognition by MAIT TCRs. (A) Backbone (ribbon) and surface representations of the structure of human MR1 (PDB ID: 4GUP) are shown in cyan. In the MR1, A′ pocket is shown the 6-FP ligand in yellow, with nitrogen atoms colored blue, and oxygen in red. The A′ and F′ pockets are labeled as such. (B) MAIT TCR recognition of MR1 presenting the stimulatory antigen, rRL (rRL-6-CH2OH) (PDB ID: 4LCC), only CDR loops of the MAIT TCR are shown, positioned in complex with MR1. CDRa loops are colored pink; CDRb are shown in blue. The rRL antigen is shown as above for 6-FP. In the insert is a zoomed view of the CDR3a (Y95) and CDR3b (E99) loop interactions with the ribtyl chain of rRL, showing the hydrogen-bonds as yellow dashes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492155&req=5

Figure 1: Molecular basis of antigen presentation by MR1 and recognition by MAIT TCRs. (A) Backbone (ribbon) and surface representations of the structure of human MR1 (PDB ID: 4GUP) are shown in cyan. In the MR1, A′ pocket is shown the 6-FP ligand in yellow, with nitrogen atoms colored blue, and oxygen in red. The A′ and F′ pockets are labeled as such. (B) MAIT TCR recognition of MR1 presenting the stimulatory antigen, rRL (rRL-6-CH2OH) (PDB ID: 4LCC), only CDR loops of the MAIT TCR are shown, positioned in complex with MR1. CDRa loops are colored pink; CDRb are shown in blue. The rRL antigen is shown as above for 6-FP. In the insert is a zoomed view of the CDR3a (Y95) and CDR3b (E99) loop interactions with the ribtyl chain of rRL, showing the hydrogen-bonds as yellow dashes.
Mentions: The structural elucidation of MR1 provided the first insight into the nature of ligands presented by this molecule (6, 32). The overall backbone structure of MR1 is most closely related to the classical class I MHC, HLA-A2; however, the antigen-presenting groove has a number of unique features. The MR1 cavity is smaller and has two pocket structures capable of binding small molecule antigens (Figure 1A). The A′ pocket, named as such due to the similarity in location to the A′ tunnels in CD1 molecules, is lined with aromatic and basic residues, creating a small, positively charged cavity that is almost entirely sequestered from external solvent. An additional pocket, termed F′ (similar in location to the F′ tunnel in CD1 molecules), is more shallow and can be variable in size due to flexibility noted in the structure of the α2 helix of human MR1(6). A comparison between the two molecules in the asymmetric unit of the human structure revealed an ~11Å shift between the positioning of the N-terminal portion of the α2 helix, with one molecule having a significantly inward-shifted helix resulting in a pseudo-collapsed F′ pocket. The structure of the A′ pocket was almost identical between the two structures, suggesting that this flexibility would not directly affect antigens presented in this pocket, although this phenomenon may shed light onto the molecular mechanisms of ligand loading. Curiously, this conformational flexibility was not apparent in the structure of bovine MR1 solved in complex with a MAIT TCR; either bovine MR1 has greater rigidity in this region or complexation with a TCR stabilizes this region of MR1(32).

Bottom Line: Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and distributed throughout the blood and mucosal sites.Studies performed in MR1-deficient mice suggest that MAIT cells can provide anti-bacterial control within the first few days post-infection, as well as contribute to enhanced adaptive immunity in murine models of respiratory infections.Given that MAIT cells are pro-inflammatory, serve in early control of bacterial infections, and appear enriched at tissue sites where microbes interface and gain access to the body, we postulate that they play an important role in antimicrobial immune responses.

View Article: PubMed Central - PubMed

Affiliation: Pulmonary and Critical Care Medicine, Oregon Health & Science University , Portland, OR , USA.

ABSTRACT
Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and distributed throughout the blood and mucosal sites. Human MAIT cells are defined by the expression of the semi-invariant TCRα chain TRAV1-2/TRAJ12/20/33 and are restricted by the non-polymorphic major histocompatibility complex (MHC) class I-like molecule, MHC-related protein 1, MR1. MAIT cells are activated by small organic molecules, derived from the riboflavin biosynthesis pathway of bacteria and fungi, presented by MR1. Traditionally, MAIT cells were thought to recognize a limited number of antigens due to usage of an invariant TCRα chain and restriction by a non-polymorphic MHC molecule. However, recent studies demonstrate that the TCR repertoire of MAIT cells is more heterogeneous, suggesting there is a more diverse array of MR1 antigens that MAIT cells can recognize. In response to infected cells, MAIT cells produce the pro-inflammatory cytokines, IFN-γ and TNF, and are cytolytic. Studies performed in MR1-deficient mice suggest that MAIT cells can provide anti-bacterial control within the first few days post-infection, as well as contribute to enhanced adaptive immunity in murine models of respiratory infections. In humans, the role of MAIT cells is unclear; however, evidence points to interplay between MAIT cells and microbial infections, including Mycobacterium tuberculosis. Given that MAIT cells are pro-inflammatory, serve in early control of bacterial infections, and appear enriched at tissue sites where microbes interface and gain access to the body, we postulate that they play an important role in antimicrobial immune responses. In this review, we discuss the most recent studies on the function and phenotype of MAIT cells, including their TCR diversity and antigenic repertoire, with a focus on the contribution of human MAIT cells in the immune response to microbial infection.

No MeSH data available.


Related in: MedlinePlus