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The Journal of Immunology, 1998, 160: 540-544.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: A Critical, Invariant Chain-Independent Role for H2-M in Antigen Presentation1

Kevin Swier2,*,{ddagger}, Daniel R. Brown2{dagger},{ddagger}, Jennifer J. Bird*,{ddagger}, W. David Martin3,§, Luc Van Kaer§ and Steven L. Reiner4,*,{dagger},{ddagger}

* Department of Medicine, {dagger} Committee on Immunology, {ddagger} Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois 60637; § Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Antigen presentation by MHC class II (class II) is facilitated by the accessory molecules, invariant chain (Ii) and H2-M. Ii associates with class II during biosynthesis and promotes transport of class II to Ag-loading compartments. One function of H2-M is the removal of Ii fragments from MHC class II. We have previously demonstrated that Ii-deficient mice, unlike class II-deficient mice, are resistant to L. major infection. In the present study, we found that H2-M-deficient (H2-M0) mice were susceptible to progressive infection with L. major. The dispensability of Ii for control of L. major allowed genetic analysis of whether H2-M functions by association with or independently of Ii. In contrast to Ii-deficient (Ii0) mice, Ii0H2-M0 mice were as susceptible to L. major as H2-M0 mice. Thus, H2-M has an essential, Ii-independent function during presentation of microbial pathogens.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The generation of a CD4+ T helper cell repertoire and expansion of Ag-specific Th cells during infection require presentation of peptides by MHC class II (class II)5. Ii and H2-M (HLA-DM in humans) are two accessory molecules necessary for efficient expression of peptide-bound class II molecules. Ii associates with class II in the ER and directs class II to endosomal compartments, where Ii is proteolytically cleaved (1). The final portion of Ii to remain associated with class II is called CLIP (class II-associated invariant chain peptide), which occupies the peptide-binding groove (2). H2-M catalyzes the release of CLIP from purified class II molecules (3, 4, 5). APCs from cell lines lacking HLA-DM (6, 7) or from mice lacking H2-M (8, 9, 10) contain class II that is predominantly associated with CLIP. In vitro studies suggest H2-M can additionally function to stabilize empty class II (11, 12) and remove suboptimal peptides (13, 14, 15, 16).

Infection of inbred strains of mice with Leishmania major is a well-established model for examining class II function. Leishmania invade macrophages and replicate within endosomal compartments that contain class II (17). Control of infection depends upon production of IFN-{gamma} by class II-restricted Th1 cells that activate macrophages to a microbicidal state (18). Class II-deficient (class II0) mice are completely susceptible to infection (19, 20, 21), whereas MHC class I-deficient mice control infection (21, 22). Ii0 mice have reduced numbers of CD4+ T cells, reduced class II expression on APCs, and inefficient presentation of Ags in vitro and in vivo (23, 24, 25, 26). Despite their impaired ability to present parasite Ags, Ii0 mice are highly resistant to infection with L. major (21). In the present study, we have used microbial immunity to define the role of H2-M. By generating Ii0H2-M0 mice we have genetically demonstrated an essential, Ii-independent role for H2-M in vivo.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

H2-M0 mice (8) and TAP-1-deficient mice (27) (from a Leishmania-resistant C57BL/6X129 background) have been previously described. C57BL/6 Class II0 (28) mice and Ii0 mice (24) were generously provided by Diane Mathis and Christophe Benoist (INSERM, France). H2-M0 mice (H-2b) were mated with Ii0 mice (H-2d congenic) to produce double heterozygous (Ii+/-H2-M+/-, H-2dxb) mice. Double heterozygotes were backcrossed to parental Ii0 mice. Transmission of the mutant H2-M allele was detected by staining peripheral blood lymphocytes using a mAb specific for the closely linked Kb molecule (Caltag Laboratories, South San Francisco, CA) while Ii+/-H2-M+/- and Ii0H2-M+/- littermates were distinguished by levels of MHC class II. Ii0H2-M+/- mice were intercrossed and Ii0H2-M0 mice were identified by homozygosity for Kb. Wild-type C57BL/6 and BALB/c mice were obtained from The Jackson Laboratory (Bar Harbor, ME). All mice were maintained in a specific pathogen-free environment before infection. All work was performed in accordance with the University of Chicago guidelines for animal use and care.

Syngeneic mixed lymphocyte reaction

CD4+ T cells from lymph nodes were enriched by depleting B220+ and CD8+ cells with mAbs and magnetic beads (PerSeptive Biosystems, Cambridge, MA). Enriched cells (1.5 x 105) were cultured in 200 µl of Iscove’s complete medium with 5 x 105 irradiated splenocytes (2500 rads) from wild-type C57BL/6 mice or on plates coated with anti-CD3 mAb (5 µg/ml). After 3 days, 1 µCi of methyl-[3H]thymidine was added, and incorporated radioactivity was measured 18 h later using a Betaplate 1205 counter (Wallac, Turku, Finland).

Flow cytometry

Single cell suspensions of lymph nodes were stained with designated mAbs specific for MHC class II I-Ab (25–9–17-FITC) and CD44 (IM7-PE) (PharMingen, San Diego, CA) as well as B220 (RA3–6B2-PE), CD4 (CT-CD4-PE), CD8 (CT-CD8{alpha}-TC), and TCR-{alpha}ß (H57–597-FITC) (Caltag Laboratories). Light scatter properties were used to gate on lymphocytes.

Leishmania infection

Leishmania major (WHOM/IR/-/173) metacyclic promastigotes (5 x 105) were injected into each hind footpad. Footpad diameter was measured weekly with a metric caliper. At termination of infection, parasite burdens in feet and spleens were determined as previously described (21).

Assay of Ag-specific cytokine production

Five x 105 popliteal lymph node cells were incubated with or without soluble extracts from freeze-thawed L. major promastigotes (100 µg/ml) in round-bottom 96-well plates. Designated cultures were supplemented with 1 x 106 irradiated C57BL/6 splenocytes as a source of APCs. IFN-{gamma} was measured by ELISA (PharMingen) from supernatants collected at 48 h.

Competitive RT-PCR analysis

RNA was extracted with Trizol Reagent (Life Technologies, Gaithersburg, MD) from unfractionated popliteal lymph node cells or purified CD4+ T cells from mice infected with L. major. RNA was reverse transcribed using random hexamer primers (Pharmacia, Piscataway, NJ) for analysis by competitive PCR as previously described (29). In brief, a polycompetitor construct containing addition-mutations of authentic cDNA was amplified in the same reaction as the experimental cDNA. When resolved on an agarose gel, the larger m.w. product served as an internal standard for comparison of the relative amounts of lower m.w. experimental cDNA between groups. Amplification for the housekeeping gene, hypoxanthine-guanine phosphoribosyl transferase (HPRT), was performed to confirm that the input cDNA was equivalent between groups.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
H2-M0 mice are susceptible to L. major infection

Control of L. major infection requires MHC class II-restricted responses (19, 20, 21). To determine the requirement for H2-M in the processing and presentation of parasite Ags, H2-M0 mice were infected with L. major. The course of disease was compared with class II0 mice, Ii0 mice, genetically susceptible BALB/c mice, and genetically resistant C57BL/6 mice. Extensive footpad lesion growth (greater than 4 mm) occurred between 4 to 6 wk in all BALB/c mice and class II0 mice (Fig. 1GoA). The onset of lesion growth was variable in H2-M0 mice, with some animals maintaining a footpad size less than 4 mm for several weeks longer than BALB/c and class II0 mice (Fig. 1GoA). By 17 wk, however, all H2-M0 mice had developed large non-healing footpad lesions (Fig. 1GoA). By contrast, no C57BL/6 wild-type or Ii0 mice developed lesions larger than 4 mm (Fig. 1AGo). Infected mice were killed at 5 wk and 9 wk postinfection for quantitation of parasite burdens. At the earlier time point, cultures from feet and spleens revealed higher parasite loads in class II0 mice compared with H2-M0 and C57BL/6 mice (Fig. 1GoB). At the later time point, however, H2-M0 mice had parasite loads comparable to class II0 mice (Fig. 1GoB). Thus, H2-M, unlike Ii, is required for efficient control of L. major infection.



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  		FIGURE 1. H2-M0 mice are susceptible to L. majorinfection. A, Lesion development in mice infected with L. major. Ii0, H2-M0, MHC class II0 (CII0), BALB/c, and C57BL/6 mice were infected as described in Materials and Methods. The percentage of mice in each group with mean hind footpad diameters less than 4 mm is depicted over time. Results are from 5 Ii0, 14 H2-M0, 3 class II0, 13 BALB/c, and 9 C57BL/6 mice infected in six separate experiments. B, Parasite burdens of infected mice. Culture results from feet and spleens of mice infected for indicated amount of time are depicted as numbers of parasites per organ from individual animals on a log10 scale. At 5 wk postinfection, 4 H2-M0, 1 class II0, and 1 C57BL/6 (B6) mice were analyzed. At 9 wk postinfection, 5 H2-M0, 2 class II0, and 2 C57BL/6 mice were analyzed. C, Assessment of Th1 responses in mice infected with L. major. Five weeks after infection, draining lymph node cells from wild-type C57BL/6 mice, infected H2-M0 mice, and uninfected H2-M0 (naive H2-M0) mice were cultured for 48 h with no additions (No Ag), L. major Ags (Ag), wild-type APCs (WT APCs), or wild-type APCs plus L. major Ags (WT APCs + Ag). IFN-{gamma} was measured from supernatants by ELISA after 48 h. Bars represent mean of triplicate cultures for individual animals with SDs as y-axis error bars. Results are representative of four separate experiments. D, Competitive PCR analysis of draining lymph node cells. RNA from unfractionated (total) or CD4+ T cells (CD4+) of draining lymph nodes of individual infected wild-type C57BL/6 (WT), and H2-M0 mice was subjected to competitive RT-PCR as described in Materials and Methods. Upper bands correspond to amplification of competitor molecule while lower bands correspond to amplification of experimental cDNA. Amplification of HPRT was done to confirm equivalent amounts of cDNA were used for amplification. Results are representative of three experiments using 4 C57BL/6 and 5 H2-M0 mice.

 
To determine whether L. major-specific Th1 responses were present in infected H2-M0 mice, we measured IFN-{gamma} produced by T cells restimulated in vitro. Draining popliteal lymph node cells from mice killed after 5 wk were cultured with or without L. major Ags. Cells from H2-M0 mice cultured with parasite Ags produced very little IFN-{gamma} (Fig. 1GoC). When wild-type APCs were added to augment Ag presentation, cells from H2-M0 mice produced IFN-{gamma} (Fig. 1GoC). Although part of the response from the cells of H2-M0 mice was due to reactivity to syngeneic APCs (8–10 and Fig. 1GoC), a small but detectable portion of the response was Leishmania Ag-specific. The Ag-specific portion of the response was not present in previously uninfected H2-M0 mice (Fig. 1GoC). Addition of anti-class II Abs to cultures blocked all production of IFN-{gamma}, (data not shown) suggesting that the response was derived from helper T cells. Analyses of numerous mice over various time points revealed an inverse relationship between footpad size and IFN-{gamma} production. To assess the Th1 response directly ex vivo we performed competitive RT-PCR on the lymph node cells of infected mice. H2-M0 mice produced discernibly less IFN-{gamma} transcripts than wild-type C57BL/6 mice (Fig. 1GoD). The IFN-{gamma} mRNA was, however, enriched by the selection of CD4+ T cells from both wild-type and H2-M0 mice. Together, these results demonstrate that H2-M0 mice generate weak Ag-specific Th1 responses to L. major that cannot sustain control of the infectious challenge.

Why is the immune response of H2-M0 mice insufficient to control infection? It is possible that the weak response cannot keep pace with the replicative capacity of the parasite because of an inability to generate sufficient IFN-{gamma} to activate infected macrophages. Alternatively, H2-M0 APCs may present altered or insufficient peptide/MHC complexes that either tolerize or fail to reactivate Ag-specific T cells. Finally, APCs may vary in their dependence on H2-M for Ag presentation. Thus, the Th1 response observed in H2-M0 mice may be stimulated by a subset of H2-M-independent APCs while a subset of H2-M-dependent APCs supports parasite growth due to an inability to redirect macrophage-activating T cells.

Analysis of lymphocytes from Ii0H2-M0mice

The inability of H2-M0 mice to control infection with L. major may result from a failure to remove CLIP from the binding cleft of class II. To analyze the function of H2-M in the absence of CLIP, we generated Ii0H2-M0 mice. We first examined the surface phenotype of lymphocytes from mice lacking Ii and/or H2-M. Staining with anti-Ab mAb, 25–9–17, showed reduced levels of MHC class II on B cells from H2-M0 mice (Fig. 2Go). This was likely due to the sensitivity of the Ab to detect conformational changes since many anti-class II mAbs stain H2-M+ and H2-M0 B cells equally well, while conformation-sensitive reagents stain H2-M0 B cells less efficiently (8, 9, 10). We observed a characteristic reduction in class II staining on Ii0 cells (23–25 and Fig. 2Go) and a slightly greater defect in class II staining on the B cells of Ii0H2-M0 mice (Fig. 2Go). H2-M0 mice and Ii0 mice both have decreased numbers of peripheral CD4+ T cells (8–10, 23–26, and Fig. 2Go). Ii0H2-M0 mice, however, had a greater reduction in CD4+ T cells than Ii0 mice (Fig. 2Go). CD4+ T cells from Ii0 mice have an abnormal surface phenotype (26), which has been attributed to inefficient positive selection (30). The defect is characterized by low levels of TCR-{alpha}ß and high levels of CD44 expression. CD4+ T cells from Ii0H2-M0 and Ii0 mice had similar abnormalities in {alpha}ß and CD44 expression (Fig. 2Go).



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  		FIGURE 2. Surface phenotype of lymphocytes from Ii0H2-M0 mice. Lymph node cells from C57BL/6 (WT), H2-M0, Ii0, and Ii0H2-M0 mice were stained with fluorescence-conjugated mAbs and analyzed by flow cytometry. MHC class II staining (far left column) was performed on B220- (thin line) and B220+ (thick line) lymphocytes. The mean fluorescence intensities of class II staining on B220+ cells were: WT, 39; H2-M0, 17.3; Ii0, 14.6; and Ii0H2-M0, 10.5. Lymphocytes were stained with mAbs specific for CD4 and CD8 (2nd column from left). Numbers next to the boxes indicate the percentage of CD4+ and CD8+ T cells. The expression of TCR-{alpha}ß (3rd column from left) and CD44 (far right column) was examined among gated CD4+ T cells. Results are representative of three separate experiments.

 
The absence of H2-M markedly alters the specificity of CD4+ T cells. The predominant expression of CLIP-bearing MHC class II molecules in the thymi of H2-M0 mice prevents the negative selection of T cells responsive to the normal array of self-peptides displayed on syngeneic wild-type APCs (8, 9, 10). To test whether the reactivity of T cells from H2-M0 mice to syngeneic APCs is due to selection on a monomorphic ligand (CLIP/Ab), we measured the proliferative response of CD4+ T cells from Ii0H2-M0 mice cultured with syngeneic wild-type APCs. Consistent with published results, T cells from H2-M0 mice proliferated strongly in response to syngeneic APCs from C57BL/6 mice (Fig. 3Go). By contrast, CD4+ T cells from Ii0H2-M0 mice, like those from wild-type mice (Fig. 3Go) and Ii0 mice (data not shown), did not proliferate in response to wild-type APCs. T cells from Ii0H2-M0 mice, however, proliferated vigorously in response to ligation with anti-CD3 (Fig. 3Go), suggesting their functional competence to respond to TCR-mediated stimuli. Thus, the absence of CLIP can correct the abnormal reactivity of T cells from H2-M0 mice, confirming an Ii-dependent role of H2-M.



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  		FIGURE 3. CD4+ T cells from Ii0H2-M0 mice do not react with wild-type syngeneic APCs. Purified CD4+ T cells from the indicated animals were cultured for 4 days with either no APCs (no stimulus), syngeneic APCs, or on plates coated with anti-CD3 mAb (5 µg/ml). Methyl-[3H]thymidine was added during the last 18 h of culture. Bars depict mean c.p.m. from triplicate cultures with SDs expressed as y-axis error bars.

 
Ii0H2-M0 mice are susceptible toL. major infection

Ii0 mice are resistant to L. major infection (Fig. 1GoA and 21 while H2-M0 mice are susceptible to infection (Fig. 1Go). If the major function of H2-M is the removal of CLIP, then the absence of Ii should rescue resistance in H2-M0 mice. To test this hypothesis, we studied the response to L. major in H2-M0 mice that lack Ii. Ii0 mice were fully resistant to infection (Fig. 4GoA). This was not due to a compensatory contribution from class I-restricted CD8+ T cells since Ii0TAP0 mice were equally resistant to infection (Fig. 4GoA). Ii0H2-M0 mice, by contrast, developed progressive footpad lesions in response to L. major infection (Fig. 4GoA). The onset of lesion development was somewhat variable in Ii0H2-M0 mice (Fig. 4GoA) and closely resembled the course of infection in H2-M0 mice that were infected simultaneously (Fig. 1GoA and data not shown). Cultures of feet and spleens of Ii0H2-M0 mice confirmed extensive local growth and visceral dissemination of the parasite, respectively (data not shown). Thus, H2-M is required for control of L. major even when class II is not occupied by Ii-derived peptides.



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  		FIGURE 4. Ii0H2-M0 mice are susceptible to L. major. A, Lesion development in mice infected with L. major. Ii0, Ii0TAP0, Ii0H2-M0, and class II0 (CII0) mice were infected with L. major, and footpad lesion size is depicted over time. Symbols represent the mean hind footpad diameter of all mice within a group except for Ii0H2-M0 mice in which symbols represent the mean of two hind footpad measurements of individual animals. The SDs of the footpad size of Ii0 and Ii0TAP0 mice were less than 25% of the mean. Results are a compilation of three experiments using 3 Ii0, 2 Ii0TAP0, 5 Ii0H2-M0, and 1 class II0 mice. At 6 wk after infection, wild-type BALB/c mice and C57BL/6 mice had mean footpad diameters of 5.9 ± 0.4 and 2.9 ± 0.3 mm, respectively. B, Assessment of Th1 responses in mice infected with L. major. Draining popliteal lymph node cells from individual C57BL/6 (B6), Ii0, and Ii0H2-M0 were cultured with no additions (No Ag), or with L. major Ags in the absence (Ag) or presence ({alpha}CII + Ag) of the anti-class II mAb M5/114. After 48 h, IFN-{gamma} was measured from supernatants by ELISA. C, Competitive PCR analysis of draining lymph node cells from mice infected with L. major. IFN-{gamma} transcripts were amplified from RNA isolated from draining lymph node cells of individual wild-type C57BL/6 (WT), H2-M0, Ii0, and Ii0H2-M0 mice using competitive RT-PCR as described in Figure 1Go.

 
The later onset of susceptibility in Ii0H2-M0 mice compared with MHC class II0 mice prompted us to test whether Th1 responses were primed in the absence of both Ii and H2-M. Lymph node cells from Ii0H2-M0 mice yielded low levels of IFN-{gamma} when restimulated with parasite Ags, and this weak Th1 response was completely inhibited by the addition of anti-class II Abs (Fig. 4GoB). Some spontaneous production of IFN-{gamma} was observed from the cells of Ii0H2-M0 and wild-type mice, which was most likely due to carry-over of L. major Ags in the lymph node APCs. Ii0H2-M0 mice also had detectable IFN-{gamma} transcripts in the draining lymph node, as assessed by competitive RT-PCR, although the levels were lower than those of Ii0 mice (Fig. 4GoC). Thus, in the absence of both Ii and H2-M, class II can still gain some access to endosomal compartments and bind antigenic peptides, but this limited function is insufficient for anti-parasitic immunity.

The susceptibility of H2-M0 and Ii0H2-M0 to L. major may result from an inability to present parasite Ags during infection or from an inability to generate normal T cells during thymic selection. In the absence of H2-M, negative selection is altered such that T cells are reactive to self-peptides presented by wild-type syngeneic APCs. This is not likely the reason H2-M0 mice are susceptible to L. major since susceptible Ii0H2-M0 mice are tolerant to wild-type syngeneic APCs (Fig. 3Go). It is also unlikely that the reduced number of CD4+ T cells in H2-M0 or Ii0H2-M0 mice results in susceptibility since the resistance of Ii0 mice is unimpeded by a relatively comparable reduction in the number of CD4+ T cells (Fig. 2Go). We, therefore, favor the explanation that H2-M0 and Ii0H2-M0 mice are susceptible to infection due to inefficient Ag presentation rather than abnormal T cell development. We are currently generating chimeric mice containing T cells from wild-type mice and APCs from Ii0H2-M0 mice to test this hypothesis.

Previous studies have revealed important functions for Ii and H2-M, two cofactors that have been evolutionarily conserved to potentiate class II function. One of the major functions of H2-M is the removal of CLIP peptides from class II molecules. By generating Ii0H2-M0 mice, we now show that there is an additional role or at least a broader specificity for H2-M in vivo. In the absence of Ii, H2-M may enhance the presentation of L. major Ags by stabilizing empty class II molecules (11, 12). In addition, H2-M may change the repertoire of Ags (31) by exchanging self-peptides with antigenic peptides (13, 14, 15, 16). Further analysis will be required to clarify the mechanisms of H2-M function in vivo.


   Acknowledgments
 
We are grateful to Michael Mahowald, Charles Brown, Elle Travis, Marisa Naujokas, and Jim Miller for helpful discussion and assistance.


   Footnotes
 
1 D.R.B. was supported by the University of Chicago Medical Scientist Training Program and Immunology Training Grant (AI-07090). W.D.M. is an Associate and L.V.K. is an Assistant Investigator of the Howard Hughes Medical Institute. S.L.R. is supported by the Burroughs Wellcome Fund and the National Institutes of Health (AI-01309). Back

2 These authors contributed equally to this work Back

3 Present address: Purdue University, West Layfayette, Indiana, 47907. Back

4 Address correspondence and reprint requests to Steven L. Reiner, Gwen Knapp Center, University of Chicago, 924 E. 57th Street, JFK R420, Chicago, IL 60637–5420. E-mail address: Back

5 Abbreviations used in this paper: Class II, MHC class II; Ii, Invariant chain; Ii0, invariant chain-deficient; H2-M0, H2-M-deficient; CLIP, class II-associated invariant chain peptide; class II0, MHC class II-deficient. Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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