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Original Article |
Sections of Infectious Diseases and Immunobiology, Yale University School of Medicine, New Haven, CT 06520.203-785-3864203-785-3561
eric.pamer{at}yale.edu
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. However, after a second L. monocytogenes infection, H2-M3–restricted memory T cell responses are minor in comparison to the much larger MHC class Ia–restricted responses. This first direct characterization of an MHC class Ib–restricted T cell response indicates that CD8+ T cells responding to L. monocytogenes infection can be divided into two groups: H2-M3–restricted responses, which provide rapid and quantitatively substantial effector function during primary infections but contribute relatively little to memory responses, and MHC class Ia–restricted responses, which expand later during primary infection but form memory T cells that respond rapidly and dramatically in response to subsequent infections by the same pathogen.
Key Words: H2-M3 • major histocompatibility complex class Ib molecules • cytotoxic T lymphocytes • Listeria monocytogenes • bacterial infection
The mammalian immune system, molded by perpetual battle with diverse and evolving pathogens, can be divided into rapid, innate responses and somewhat delayed adaptive responses. Innate immunity targets microbial products that have been conserved through evolution and are shared by many microorganisms 1. The innate immune system uses germline-encoded molecules to quickly respond to a wide variety of pathogens. Many mechanisms have evolved to specifically identify bacterial products: LPS, a product of all gram-negative bacteria, is recognized by several molecules of the immune system, including LPS binding protein 2, CD14 3, and CD11c/CD18 4; macrophage scavenger receptors detect components of both gram-positive and gram-negative bacterial cell walls as well as the intact pathogens 56; and the N-formyl peptide receptor, found on neutrophils and macrophages, binds peptides starting with N-formyl methionine, the amino acid that initiates prokaryotic protein synthesis 7. These and perhaps many other molecules provide early detection of invading bacteria, thereby initiating antimicrobial defense and providing important cues for the developing adaptive immune response.
The adaptive, or specific immune system targets antigens expressed by a vast array of pathogens by generating B and T cell clones that each bear a rearranged specific antigen receptor 8. CD8+ T cells constitute an important arm of the adaptive immune response, recognizing pathogen-derived peptides that are presented by MHC class I molecules 9. MHC class I molecules have generally been divided into two groups: members of the highly polymorphic class Ia family present many different peptides to CD8+ T cells and have well-defined roles in immune defense against infection, whereas the function of molecules belonging to the more conserved MHC class Ib family has remained somewhat less clear 101112. However, two different nonpolymorphic class Ib molecules appear specially suited for presentation of bacterial products. The divergent class Ib molecule CD1 is found outside the MHC locus in both humans and mice but is similar to MHC-encoded class I molecules in its structure and association with β2-microglobulin (β2m)1 1314. Human CD1b presents mycobacterial glycolipids, such as Mycobacterium tuberculosis–derived mycolic acids 15 and Mycobacterium leprae–derived lipoarabinomannan 16, to unique subsets of T cells. Murine CD1d1 has a deep, hydrophobic binding groove 14; it is known to bind hydrophobic peptides of varying lengths and appears ideal to bind lipids and glycolipids as well.
The other murine class Ib molecule involved in antibacterial immunity, H2-M3, shows a strong preference for binding N-formyl peptides 12. N-formyl methionine is the initiating amino acid for bacterial protein synthesis, while in mammals only mitochondria use this amino acid. Thus, like CD1, H2-M3 seems ideally suited for the presentation of bacterial antigen to T cells. Unlike CD1, H2-M3 is encoded within the MHC and is believed to present only peptide antigen. Crystallographic study of H2-M3 revealed that the molecule has a structure very similar to that of MHC class Ia molecules, although the peptide groove is more hydrophobic, and the A pocket, which holds the first peptide residue in most class I molecules, is blocked 17. Binding of NH2-terminal formyl methionine occurs in the B pocket, and, as a consequence, peptides bound to H2-M3 are relatively short in comparison to the 8- to 10-mers that associate with class Ia molecules.
Early studies of T cell responses to infection with the gram-positive bacterium Listeria monocytogenes demonstrated the prominent role of CD8+ T cells in adaptive immunity to the pathogen 18, and multiple Listeria-derived antigens recognized by MHC class Ia–restricted CD8+ T cells have been identified 19. Bacterial peptides are also presented in the context of the MHC class Ib molecule, H2-M3 2021, a finding which explained the interesting observation that some CD8+ T cells recognize L. monocytogenes–infected cells in the absence of classical MHC restriction 22. Three N-formylated peptides derived from L. monocytogenes and presented to CD8+ T cells by H2-M3 have been identified 232425. Despite the potential importance of H2-M3–restricted CD8+ T cells in immunity to bacterial infection, their contribution relative to MHC class Ia–restricted responses remains unclear.
In this study, we investigate the H2-M3–restricted T cell response specific for one of the L. monocytogenes–derived N-formyl peptides, f-MIGWIIA 23, and compare it to the well-characterized H2-Kd–restricted, listeriolysin O (LLO)91–99 specific T cell response. We show that H2-M3–restricted responses to L. monocytogenes are kinetically distinct from class Ia–restricted responses; functional CD8+ CTLs specific for f-MIGWIIA become apparent and reach a climax earlier than LLO91–99 specific T cells. Memory responses of H2-M3–restricted T cells are also distinctive; while LLO91–99 specific (class Ia–restricted) T cells undergo very dramatic, rapid expansion upon reinfection with L. monocytogenes, relatively few f-MIGWIIA–specific cells are detected during the recall response. These findings demonstrate that T cell responses restricted by H2-M3 are distinct from those restricted by class Ia molecules and suggest that H2-M3–restricted T cells may have a unique, early role in immune responses against primary bacterial infection while playing a relatively minor role in memory responses.
Generation of H2-M3 Tetramers.
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Mice, Bacteria, and Listeria Infection.
Female CB6/F1, BALB/c, C57BL/6, and C3H/HeJ mice were purchased from The Jackson Laboratory. L. monocytogenes strain 10403s was obtained from Daniel Portnoy (University of California Berkeley, Berkeley, CA) and grown in brain–heart infusion broth. Mice 8–12 wk old were infected by tail vein injection with 2 x 103 L. monocytogenes for primary infection. Recall infection with 105 bacteria was performed 7 wk after primary infection. Splenocytes were harvested at different time points during the course of infection as described previously 26.
H2-M3 tetramers were generated following the approach described previously 2627. The cDNA for mouse β2m was provided by Pamela Bjorkman (California Institute of Technology, Pasadena, CA) and amplified with the following primers: 5'-GGCATATGATCCAGAAAACCCCTCAA-3' and 5'-CCGGATCCTACATGTCTCGATCCCAGTA-3'. The full-length cDNA clone for H2-M3 was obtained from Chyung-Ru Wang (University of Chicago, Chicago, IL) and modified and amplified by PCR. The following primers were used: 5'-GGCATATGGGTTCACATTCATTACGTTATTTCCACACTGCG-3' and 5'-CCGGATCCTAATCGCGCAGCTCCATCTTCATAGCCTCGAAGATACCACCCAGAC-CACCACCCCATTTCAGGGCAAGGGG-3'. The former, NH2-terminal primer, removed the leader sequence. The latter, COOH-terminal primer, replaced the transmembrane and cytoplasmic domains with a biotinylation sequence. The initial H2-M3 sequence was modified to replace four C or G nucleotides at the NH2 terminus with A or T, after the construct failed to produce significant protein in Escherichia coli (see Fig. 1 A). This approach, used to increase expression of eukaryotic proteins in bacteria, was described previously by Garboczi et al. 28. Four nucleotides were changed as follows (changes underlined): ATG GGC TCA CAT TCA CTG CGC to ATG GGT TCA CAT TCA TTA CGT. The changes did not alter the amino acid sequence. PCR products were cloned into the pET3a isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible vector (Novagen, Inc.) and expressed as recombinant proteins in the E. coli expression host BL21(DE3). H2-M3 heavy chain and β2m were purified from inclusion bodies as described previously 26, dissolved in 8 M urea, and refolded in the presence (or absence) of 
60 µg/ml f-MIGWIIA or f-MFINRW (cytochrome c oxidase subunit I [COI]) peptide (Research Genetics Inc.) and the protease inhibitors pepstatin (1 µg/ml), leupeptin (1 µg/ml), and PMSF (0.4 mM). Soluble monomeric H2-M3/β2m/peptide complexes were purified by gel filtration over a Superdex 200HR column (Amersham Pharmacia Biotech). Purified monomeric complexes were biotinylated in vitro at 20°C for 12 h in the presence of 15 µg BirA enzyme (Avidity), 80 µM biotin, 10 mM ATP, 10 mM MgOAc, 20 mM bicine, and 10 mM Tris-HCl (pH 8.3). Complexes were purified again by gel filtration to remove excess biotin and tetramerized with PE-conjugated streptavidin (Molecular Probes, Inc.) at a 4:1 molar ratio. Finally, tetramers were purified by gel filtration and stored at a concentration of 5 mg/ml at 4°C in PBS (pH 8.0) with 0.02% sodium azide, 1 µg/ml pepstatin, 1 µg/ml leupeptin, and 0.5 mM EDTA. H2-Kd/LLO91–99 tetrameric complexes were produced as described previously 2627.
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Enrichment, Staining, and Analysis of CD8+ T Cells.
Splenocytes were enriched for CD8+ T cells by depletion using magnetically activated cell sorting (MACS®; Miltenyi Biotec). Cells were first incubated with antibodies against CD4 (GK1.5), MHC class II (TIB120), and MAC-1 (TIB128) for 20 min on ice in separation buffer (PBS, 0.5% BSA, and 2 mM EDTA, pH 7.45). After extensive washing, spleen cells were incubated with goat anti–rat IgG magnetic microbeads (Miltenyi Biotec) for 20 min at 4°C. Splenocytes were washed again, applied to a type LS column (Miltenyi Biotec), and separated using the MidiMACS® (Miltenyi Biotec) following the manufacturer's instructions. For staining, 3 x 105 CD8+-enriched splenocytes were blocked with unconjugated streptavidin (0.5 mg/ml; Molecular Probes, Inc.) and Fc-block (PharMingen) in staining buffer (SB; PBS, 0.5% BSA, 0.02% sodium azide, pH 7.45) in a 96-well plate for 20 min on ice. Cells were then triple stained with anti-CD62L–FITC (clone MEL-14; PharMingen); PE-conjugated H2-M3/f-MIGWIIA, H2-M3/COI, or H2-Kd/LLO91–99 tetrameric complexes (0.25–0.5 mg/ml); and anti-CD8
–CyChr (clone 53-6.7; PharMingen) in SB for 1 h on ice. After three washes in SB, cells were fixed in 1% paraformaldehyde/PBS (pH 7.45). Data were acquired using a FACSCaliburTM flow cytometer and analyzed using CELLQuest software (Becton Dickinson). For cell sorting, staining of enriched CD8+ T cells from each spleen was performed in a single tube using a staining buffer of PBS supplemented with 0.5% FCS, and cells were not fixed before sorting.
Chromium-release Assays.
P815 target cells (American Type Culture Collection) were labeled with 51Cr and washed. FACS®-sorted cells were incubated with 5 x 103 labeled cells alone or in the presence of 10–6 M f-MIGWIIA, f-MFINRW (COI self), or LLO91–99 peptide for 7.5 h at 37°C. The percent specific lysis was calculated as described previously 26 based on the amount of 51Cr release.
Enzyme-linked Immunospot Assay.
The enzyme-linked immunospot (ELISPOT) assay for detecting IFN-–producing T cells was performed as described previously 29. In brief, P815 target cells were irradiated (10,000 rads) and coated with 10–6 M f-MIGWIIA or LLO91–99 peptide, or incubated in the absence of peptide, for 1 h at 37°C. After washing, 105 target cells were added along with 105 immune splenocytes to each well of a 96-well nitrocellulose plate (Millipore, Inc.) coated with anti–IFN- antibody (clone R4-6A2; PharMingen). The plate was incubated for 24 h at 37°C in the presence of 30 U/ml IL-2. IFN- production was detected with biotin-labeled anti–IFN- antibody (clone XMG1.2; PharMingen), followed by addition of streptavidin peroxidase (Kirkegaard & Perry Labs., Inc.) and development with a substrate solution of 1 mg/ml DAB (HRP Color Development Reagent; Bio-Rad Laboratories), 50 mM Tris-HCl, and 0.5 µl/ml 30% hydrogen peroxide. Spots were counted under a dissecting microscope.
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To ensure that refolding and stabilization of soluble H2-M3 complexes were peptide dependent, refolding reactions were performed in the absence of peptide (Fig. 1 E) or in the presence of f-MIGWIIA (Fig. 1 C) or COI (Fig. 1 D) peptide. Size-exclusion chromatography demonstrated that heavy chain and β2m form stable complexes in the presence (Fig. 1C and Fig. D) but not the absence (Fig. 1 E) of N-formylated peptide. Purified H2-M3 complexes were biotinylated and tetramerized with PE-conjugated streptavidin. Tetrameric complexes were further purified by gel filtration before concentration and used as staining reagents for flow cytometric analyses 27.
Staining and Specificity of H2-M3 Tetramers.
Tetrameric complexes refolded with the L. monocytogenes–derived f-MIGWIIA peptide were tested for specific staining of in vitro peptide-restimulated CTL lines and clones generated from L. monocytogenes–infected mice. All CTL lines and clones specifically killed target cells coated with the stimulating peptide when tested in chromium-release assays (data not shown). f-MIGWIIA–specific CTL lines derived from both C57BL/6 and BALB/c mouse strains demonstrated high intensity staining with H2-M3/f-MIGWIIA tetramers (Fig. 2A and Fig. B). Within some CTL lines, particularly those stimulated in vitro for a short time, a fraction of cells stained with low intensity or did not stain with the tetramers (Fig. 2 B, and data not shown). However, all three f-MIGWIIA–specific CTL clones stained with uniformly high intensity with H2-M3/f-MIGWIIA tetramers (Fig. 2 C, and data not shown). These data indicate that although H2-M3/f-MIGWIIA tetramers stain most f-MIGWIIA–specific CTLs, a small portion of T cells, perhaps those with lower affinity for the MHC/peptide complex, may not be detected. H2-M3/f-MIGWIIA tetramers did not stain CTLs specific for the H2-Kd–restricted peptide LLO91–99 (Fig. 2 D), demonstrating their specificity in staining, similar to the findings for H2-Kd/LLO91–99 tetramers (26; Fig. 2A–C). Some CTL lines specific for the other Listeria-derived, N-formylated peptides stained, to varying but generally small degrees, with H2-M3/f-MIGWIIA tetramers (data not shown). This staining correlated with cross-reactive killing in CTL assays and is not entirely surprising, given the cross-reactivity in recognition of N-formylated peptides demonstrated by Nataraj et al. 33. No staining of cell lines was detected with H2-M3 tetramers refolded with the COI self-peptide (data not shown). These studies show that H2-M3/f-MIGWIIA tetramers can be used to stain f-MIGWIIA–specific T cell populations and demonstrate that the staining is specific.
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2 d in several studies (Fig. 3 and Fig. 4, and data not shown). Indeed, in the strain comparison reported here (Fig. 3), f-MIGWIIA–specific cells from three strains synchronously peaked on day 7 after infection (Fig. 3 B), whereas LLO91–99 specific cells in H2d BALB/c mice reached their highest magnitude around day 9 after infection (data not shown). These experiments indicate that although magnitude and exact kinetics of H2-M3–restricted responses vary somewhat among mice investigated, f-MIGWIIA–specific CD8+ T cell populations respond earlier than H2-Kd–restricted T cell populations upon infection with L. monocytogenes.
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5 d after infection, the magnitude of the f-MIGWIIA–specific T cell population after reinfection was lower than the peak primary response specific for the peptide and >10-fold lower than the recall LLO91–99 specific T cell response in the same mouse (Fig. 5 and Fig. 6B). Similar results were obtained in the B10.D2 mouse strain (data not shown). These experiments show that H2-M3– and H2-Kd–restricted T cell populations differ greatly in their extent of expansion after reinfection with L. monocytogenes. In addition, unlike the primary response, during which f-MIGWIIA and the LLO91–99 specific T cell responses have remarkably different timing in expansion and contraction, after reinfection with L. monocytogenes, the two populations have similar kinetics.
Functional Qualities of H2-M3–restricted T Cells.
The previous experiments described in this report demonstrate that Listeria-specific H2-M3–restricted T cells are detectable and peak earlier than H2-Kd–restricted responses after primary infection, but they do not indicate whether this early expansion might have implications for bacterial clearance. To determine whether H2-M3–restricted L. monocytogenes–specific T cells present 5 d after primary infection have characteristics of functional CD8+ T cells, we placed immune splenocytes directly into a chromium-release assay to assess cytolytic ability (Fig. 7 A) and an ELISPOT assay to detect IFN- production (Fig. 7 B). FACS®-sorted CD62Llow (activated), f-MIGWIIA–specific CD8+ T cells demonstrated significant specific killing activity against f-MIGWIIA–coated target cells (Fig. 7 A, left panel). Splenocytes depleted of H2-M3/f-MIGWIIA tetramer–staining cells (Fig. 7 A, right panel) had little activity against f-MIGWIIA peptide, indicating that essentially all f-MIGWIIA–specific T cells were detected with the tetramers. No LLO91–99 specific killing activity was detected at this early time point after infection. Splenocytes from another mouse were stained with H2-Kd/LLO91–99 tetramers at the same time and subjected to an identical sorting process for tetramer-positive and tetramer-negative cells within the CD8+CD62Llow population. Too few H2-Kd/LLO91–99 tetramer–positive cells were detected to sort effectively. However, within the tetramer-negative population, significant f-MIGWIIA–specific killing was found, with >15% specific lysis of target cells (data not shown). H2-M3–restricted T cells also secreted IFN- 5 d after primary infection (Fig. 7 B). Approximately four times more IFN-–secreting f-MIGWIIA peptide–specific cells than LLO91–99 specific cells were detected. These experiments demonstrate that H2-M3–restricted T cells detected early (day 5) after primary infection are functional CD8+ T cells, with both cytolytic and IFN-–secreting abilities.
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Why do H2-M3–restricted T cells expand more rapidly during a primary immune response to L. monocytogenes than other T cells? One possibility is that N-formylated peptides are presented earlier during infection than other epitopes, giving H2-M3–restricted T cells a temporal advantage over other T cells. The efficiency of L. monocytogenes N-formyl peptide presentation by H2-M3 is not known. However, bacterially secreted N-formyl peptides are likely to require much less processing to be presented by class I molecules than epitopes occupying internal positions in proteins. In addition, it is known that H2-M3 is poorly represented on the cell surface due to the paucity of mitochondrial self-peptides 36. Therefore, it is possible that bacterial infection induces the surface expression of H2-M3 due to a sudden abundance of N-formylated peptides. In this setting, bacterially derived N-formylated epitopes could be presented quickly, whereas presentation of bacterial peptides bound by class Ia molecules might be delayed as they compete for presentation with a plethora of self-peptides. Although these mechanisms might provide H2-M3–restricted T cells with a relative time advantage, it seems unlikely that they could account for the 2-d lead over the H2-Kd–restricted T cell responses.
An alternative explanation for the early response of H2-M3–restricted T cells is that they may have been primed in vivo before L. monocytogenes infection. Indeed, in its relatively rapid expansion after L. monocytogenes infection, the H2-M3–restricted T cell response more closely resembles a memory response than a primary response to antigen. The notion that commensal bacteria may prime H2-M3–restricted T cells was proposed by Lenz and Bevan when they found that mice housed in non-specific pathogen–free (SPF) facilities had established immunity to the Listeria-derived f-MIGWII and f-MIVIL peptides in the absence of previous infection with L. monocytogenes 37. We have also noted that older mice often generate larger H2-M3–restricted T cell responses than younger mice (Kerksiek, K., and E.G. Pamer, unpublished results), suggesting that exposure to environmental bacteria, such as the normal flora of the gut, may modulate the repertoire of T cells specific for foreign bacteria. This hypothesis requires the assumption that environmental bacteria either express the same formyl peptides expressed by L. monocytogenes and other foreign bacteria, or that formyl peptides are promiscuously recognized by H2-M3–restricted T cells, perhaps due to their relative shortness or hydrophobicity. Recent studies of f-MIGWII–specific T cell clones demonstrated a remarkable degree of peptide cross-recognition, supporting the latter of these two possibilities 33. Although T cells responding to f-MIGWIIA display the characteristic memory phenotype of rapid in vivo expansion, further experiments will have to be performed to dissect the role of bacterial exposure in the generation of H2-M3–restricted T cell responses.
Although a relatively rapid H2-M3–restricted T cell response is generated during primary infection with L. monocytogenes, these cells do not expand dramatically upon reinfection with the bacterium. It is possible that H2-M3–restricted memory T cells are not generated during the primary immune response or are not maintained after the resolution of infection. However, our tetramer stainings, while near the limits of detection, suggest that f-MIGWIIA– and LLO91–99 specific T cells are present at comparable levels 7 wk after primary infection. We favor the possibility that expansion of H2-M3–restricted memory T cells requires a greater duration of antigen exposure than required by LLO91–99 specific T cells, which undergo dramatic in vivo expansion after reinfection. Bacterial infection during the recall response is limited to 1 or 2 d (26; and data not shown), which might be insufficient for f-MIGWIIA–specific T cell expansion. Thus, while a "memory response" during primary infection and the lack of such during recall infection may appear paradoxical, the vastly different kinetics of bacterial infection in these two circumstances may provide an explanation.
Common laboratory mouse strains share the same H2-M3 allele and should therefore be capable of generating functional H2-M3–restricted T cells in response to bacterial infection. Indeed, all of the mouse strains investigated here show such a response. However, the magnitudes of these responses differed quite dramatically; in particular, BALB/c mice generated significantly fewer H2-M3–restricted, L. monocytogenes–specific T cells than did C57BL/6 and C3H/HeJ mice. There are several reasons why these differences might occur. One possibility is that thymic or peripheral selection of the T cells occurs differently among these mouse strains; it is unclear how the repertoire of H2-M3–restricted T cells is selected 12. If selection of H2-M3–restricted T cells occurs on H2-M3/self-peptide complexes expressed in the thymus, the different mouse strains should possess similar repertoires, as the same mitochondrial proteins are present in these strains. However, if the repertoire of H2-M3–restricted cells is influenced by resident bacterial flora such as those found in the gut, then distinct subsets of H2-M3–restricted T cells might be selected in different mouse strains. Another factor that might account for the varied H2-M3–restricted T cell responses in different mouse strains is the genetic background of the host. Indeed, mouse strains are known to vary dramatically in susceptibility to L. monocytogenes infection 38, and the basis for this remains largely unexplored. It is possible that complex genetic factors that influence infectious disease susceptibility can affect the magnitude of T cell responses.
Primary L. monocytogenes infection of immunocompetent mice generally resolves within 6–7 d. Although CD8+ T cells are known to be important in the clearance of infection, maximal T cell responses restricted by H2-Kd occur after the infection has been cured. However, H2-M3–restricted CD8+ T cells respond to primary L. monocytogenes infection 2 d earlier than their MHC class Ia–restricted cousins, resulting in significant numbers of cytolytic, IFN-–producing H2-M3–restricted T cells on the fifth day after infection (Fig. 7). This finding suggests that H2-M3–restricted T cells play an important role in the early control of primary infection with L. monocytogenes. Remarkably, although the H2-M3–restricted T cell population appears very vigorous during primary infection, MHC class Ia–restricted T cells seem to be more important for providing T cell memory. This is the first demonstration, to our knowledge, of temporal diversity and differential memory capacity within CD8+ T cell populations responding to bacterial infection.
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Submitted: 12 February 1999
Revised: 14 April 1999
Accepted: 17 May 1999
K.M. Kerksiek is supported by National Institutes of Health Training Grant 5T32-AI07019. D.H. Busch is a recipient of a Howard Hughes Fellowship for Physicians. This work was supported by Public Health Service Grant 1RO1 AI-42135.
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