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T Cells rather than CD4 T Cells during Mycobacterium tuberculosis Infection1
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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Abstract |
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T cells and other non-CD4+CD8+ cells, rather than CD4 T cells. The production of IL-17 by these cells is stimulated by IL-23 alone, and strongly induced by the cytokines, including IL-23, produced by M. tuberculosis-infected dendritic cells. IL-23 is present in the lungs early in infection and the IL-17-producing cells, such as T cells, may represent a central innate protective response to pulmonary infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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production in mice (1, 3). A new subset of CD4 helper cells, distinct from that of Th1 and Th2 cells, termed Th17, has been described (4, 5). The development of this IL-17-producing subset is inhibited by IFN- or IL-4, and may be involved in autoimmune diseases. However, mature Th17 cells are resistant to the effects of IL-4 and IFN-, and are able to secrete IL-17 in Th1 or Th2 environments (4). Overexpression of IL-17 in lung epithelium results in lung pathology including epithelial hypertrophy and the presence of multinucleated macrophages in the parenchyma (5). IL-23 induction of IL-17 in the lung leads to downstream events that mobilize cell infiltration. IL-17 induces chemokines, growth factors, and adhesion molecules, and augments neutrophil accumulation (6, 7). It has been demonstrated to play a role in control of pulmonary infection due to Klebsiella, an extracellular bacterial pathogen, in mouse models.
There are several lines of evidence that suggest cells contribute to the immune response to Mycobacterium tuberculosis. In the macaque model of infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG),3 the V2V2+ T cell subset expand rapidly during primary exposure and also to secondary challenge with BCG or virulent M. tuberculosis (8). Similarly, intranasal infection of mice expanded resident V2 T cells and caused an influx of other subsets into the lung. These cells were capable of producing IFN- and were cytotoxic toward infected macrophages in vitro (9). In humans, cells from BCG-vaccinated individuals expand upon restimulation with mycobacterial Ag, thereby displaying a memory-like phenotype (10). Human alveolar macrophages infected with M. tuberculosis release chemoattractants such as CXCL10 that cause chemotaxis of cells and cytokine secretion (11). These chemoattractants are found in the lungs and axillary lymph nodes of patients with active disease. In the mouse model of M. tuberculosis infection, knockout (KO) mice have a more pyogenic granulomatous response, implying a regulatory role in granuloma formation (12).
IL-12 has a central role in priming T cells to produce IFN- in response to M. tuberculosis (13, 14). IL-23 also contributes to resistance as suggested by the increased susceptibility of IL-12p40–/– compared with IL-12p35–/– mice during experimental infection (15). Somewhat surprisingly in light of that study, mice deficient in the p19 subunit of IL-23 did not display obviously increased susceptibility to M. tuberculosis (as measured by bacterial numbers). The relatively less susceptible phenotype of IL-12p35–/– mice may be due to the fact that IL-23 can also make a minor contribution to IFN- production in the absence of IL-12 (16). It was also demonstrated that IL-23 is an absolute requirement in CD4+ T cell production of IL-17 during M. tuberculosis infection (16). The role of the IL-17-producing T cells in control of M. tuberculosis infection is not known.
In this study, we have used murine M. tuberculosis infection as a model to investigate the interaction between IL-23 and IL-17, with particular emphasis on the cells that respond to IL-23. By using a slow growing bacterium against which immune responses develop slowly, we have dissected the early IL-17 responses in the lungs, and the chronicity of cytokine production.
Recently, a homeostatic loop involving IL-23-induced IL-17 production by unconventional 
T cells and cells has been described (17). Whereas IL-23 and IL-17 promote granulopoiesis and influx of neutrophils into the lung, phagocytosis of apoptotic lung neutrophils reduces macrophage IL-23 secretion, and induction of IL-17, thereby limiting influx. The data presented here similarly demonstrate that, in naive mice, IL-17 production can be induced in T cells. However, our study also demonstrates that M. tuberculosis infection of dendritic cells (DC) significantly increases production of IL-23 and other soluble factors. These factors drive the production of IL-17 from T cells but surprisingly not from CD4 T cells. IL-23 is also present in the lungs early in infection. Production of IL-17 by T cells occurs before Ag-specific T cell priming or substantive IFN- production, consistent with a role in early lung remodeling and resistance to infection. Although CD4 Th17 cells appear in the lung as the infection progresses, the main contributors of IL-17 throughout the course of M. tuberculosis infection were non-CD4/CD8 cells, including T cells. These results support a role for IL-23 and IL-17 involving T cells as a first line of defense or inflammation before CD4 T cell responses are acquired, and suggest that the IL-23/IL17 homeostatic loop behaves as a proinflammatory network during infection and that non-CD4+ T cells and T cells can assume a dominant role in IL-17 production when CD4+ T cells have been primed for IFN- production.
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Materials and Methods |
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Bone marrow cells from C57BL/6 mice were cultured in DMEM supplemented with 10% FBS, 1000 U/ml GM-CSF, and 1000 U/ml IL-4. Cytokines were replenished on day 3 of culture. On the sixth day of culture, the cells were plated at 1 x 106/ml and the medium was replenished without IL-4. DC were infected with M. tuberculosis strain Erdman at a multiplicity of infection of 3 for 18 h. Cells and supernatants were harvested by centrifugation.
Mice and bacteria
Female 6- to 8-wk-old C57BL/6 mice were infected via aerosol with 
50 CFU of M. tuberculosis strain Erdman as described previously (18). Mice deficient in TCR expression (strain name, B6.129P2-Tcrdtm1Mom/J) were purchased from The Jackson Laboratory. Breeding pairs of mice deficient in IL-12p40 or IL-12p35 were obtained from Dr. J. Kolls (University of Pittsburgh, Pittsburgh, PA), and bred as homozygotes in our breeding facility under specific pathogen-free conditions. For CFU determination, mice were euthanized at different time points and organ homogenates were plated on 7H10 plates and incubated for 3 wk at 37°C/5% CO2. All animal procedures were approved by the University of Pittsburgh Institutional Animal Care Committee.
ELISPOT and protein analysis
Lung cells and spleens cells were obtained by crushing whole organs through cell strainers, washing with PBS, and lysing RBC as described previously (19). Cell yields were typically 1 x 106 live cells per naive lung, increasing 4- to 5-fold during the chronic phase of infection (4 wk). ELISPOT plates (Millipore 96-well MultiScreen HTS) were coated with 15 µg/ml anti-mouse IL-17A specific mAb (clone 50101; R&D Systems) or anti-mouse IFN- mAb (BD Biosciences) in PBS. IL-2 (PeproTech) was added to a final concentration of 30 U/ml, and cells were incubated for 48 h at 37°C/5% CO2. Cells were usually plated at 2 x 105 cells/well, except for purified cells, which were plated at lower concentrations due to low availability, and then normalized to 25,000 cells. Cytokines were detected with biotinylated anti-mouse IL-17 (R&D Systems) or anti-mouse IFN- Ab (BD Biosciences) and developed with avidin peroxidase and AEC substrate (Vectastain PK6100, PK4200). ELISPOT plates were read on an automatic ELISPOT reader (ImmunoSpot; Cellular Technology). Analysis of cytokine concentration from cell supernatants was done using a Bioplex Suspension Array (Bio-Rad Laboratories) and a Luminex reader according to the manufacturer’s instructions.
Cell purification
In initial experiments, CD90+, CD4+, CD8+, B220+, and CD11b+ cells were positively selected by direct labeling with MicroBeads, and cells selected by indirect labeling with anti--TCR-biotin, and then anti-biotin MicroBeads (Miltenyi Biotec). Cell fractionation was confirmed by FACS. Spleen and lung cells that were depleted of both CD4+ T cells and CD8+ T cells contained cells that stained positively for B220, NK1.1, CD11b, TCR, and CD3, and were negative for CD4 and CD8. In subsequent experiments, cells were purified by FACS sorting on a FACSAria (BD Biosciences).
Statistical analyses
All statistical analyses were performed using GraphPad Prism for Windows, version 4.03 (GraphPad Software). A one-way ANOVA followed by a Tukey posttest was used to determine significance. Values of p < 0.05 were considered significant.
Adenovirus
A lymphocytic choriomeningitis virus internal ribosomal entry sequence was cloned between the IL-23 p19 subunit and the IL-12/23 p40 subunit in pAd/CMV/V5 (Invitrogen Life Technologies). This construct was used to create adenovirus secreting active IL-23 as previously described (20).
Flow cytometry
Lung and spleen cells were obtained by crushing through cell strainers as described previously (19). For intracellular staining, lung and spleen cells were stimulated with 500 ng/ml ionomycin and 50 ng/ml PMA, in the presence of 3 µM monensin (Sigma-Aldrich) for 4–6 h. Cells were stained for surface markers with anti-CD4 (clone RM4-5), and anti-(TCR) chain (clone GL3) Abs, fixed with 4% paraformaldehyde, permeabilized, and stained with anti-IL-17 (clone TC11-18H10) and anti-IFN- (clone XMG1.2; BD Pharmingen) Abs. Cells were analyzed using a FACSCalibur flow cytometer (BD Biosciences) and FlowJo software (Tree Star).
For purification, lung and spleen cells were stained with anti-CD3, anti-CD4, and anti- TCR, and sorted on a FACSAria flow cytometer (BD Biosciences) in the BSL3 facility.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Infection with a low dose of M. tuberculosis via aerosol results in the slow priming of IFN--producing CD4 T cells, with responses detected in the mediastinal lymph node by 2 wk postinfection (21, 22). These cells, along with M. tuberculosis-specific CD8 T cells, traffic to the lungs between 2 and 3 wk postinfection, and control but do not eliminate the infection. We were interested in examining the production of IL-17 by the T cells in response to M. tuberculosis infection, based on reports that IL-23 may be an important mediator of control in this infection (15, 23).
Cells obtained from the lungs were stimulated with infected DC in an ELISPOT format for IL-17. In the ELISPOT assay, IL-17 production was easily detected in lung cells stimulated with M. tuberculosis-infected (but not uninfected) DC (Fig. 1). IL-17 production could also be detected in the absence of DC when lung cells were stimulated with culture supernatant from infected DC. In contrast to IL-17 production, IFN- production was reduced without exogenous infected DC as APC, and was not induced by the DC supernatant alone. IL-17 production from lung cells could also be triggered by DC transfected with adenovirus that expressed IL-23. Addition of neutralizing anti-IL-12/23p40 Ab to the infected DC supernatants inhibited the production of IL-17 (Fig. 1C).
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Production of IL-23 by M. tuberculosis-infected DC induces IL-17 from lymphocytes
Because the supernatant from M. tuberculosis-infected DC was so effective at inducing IL-17 production, even from naive cells, the inflammatory cytokines produced in the first 24 h following DC infection were characterized. As expected, M. tuberculosis infection induced proinflammatory cytokines and chemokines, including IL-1, IL-1, G-CSF, CCL3/MIP-1, keratinocyte-derived chemokine, CCL5/RANTES, and TNF- (Table I). There was appreciable production of the shared subunit of IL-12 and IL-23 (p40), but only modest IL-12p70 was induced upon infection. These results were consistent with the secretion of IL-23 during infection with M. tuberculosis.
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from the naive cells (data not shown).
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T cells are a source of IL-17 in naive mice
It has recently been shown that T cells are involved in a homeostatic loop involving IL-23-induced IL-17 (17). Because the source of IL-17 was in the lymphocyte subset, and most of the IL-17 was not produced by CD4+ or CD8+ T cells in naive mice, we hypothesized that T cells were one possible source of IL-17. CD90+ spleen cells from uninfected wild-type and KO mice were compared for IL-17 production by ELISPOT.
The number of IL-17-producing cells was significantly reduced in the –/– mice compared with wild-type CD90+ cells (Fig. 4A). This activity was also inhibited by anti-IL-12/23p40 Ab (Fig. 4A). Similarly, when the KO CD90+ spleen cells were stimulated with AdIL-23, there was a reduced frequency of IL-17-producing cells compared wild-type CD90+ cells (Fig. 4B). These results support that T cells were a substantial source of IL-17 produced in response to IL-23 from M. tuberculosis-infected DC.
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T cells as well as other non-CD4+ T cells are major producers of IL-17 in response to M. tuberculosis infection
Although T cells were a major source of IL-17 in uninfected mice, the contribution of these cells to IL-17 production during M. tuberculosis infection was unknown. The data from the KO mice suggested that there were subsets in addition to T cells that produced IL-17. We followed up these studies in M. tuberculosis-infected mice, and purified cells from the lungs and spleen of infected mice at various time points (2, 4, and 52 wk postinfection), using microbeads, into fractions containing 1) CD4+, CD8+, B cells and macrophages ("CD4 pool"); 2) T cells; or 3) all other cells ("flow through"). This latter fraction contained NK cells, NK T cells, and other cell types (data not shown). These cells were stimulated with supernatant from uninfected or infected DC, and tested for IL-17 production by ELISPOT (Fig. 5). The T cell fraction and the flow-through fraction both contained cells capable of producing IL-17 in response to DC supernatant, at a higher frequency than CD4+ T cells. Thus, T cells as well as other non-CD4+ or -CD8+ cells can produce IL-17 during M. tuberculosis infection.
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T cells to IL-17 production during M. tuberculosis infection, CD4+ and cells were purified from spleens at 2 and 4 wk postinfection, and from the lungs at 4 wk postinfection by FACSAria (Fig. 6A). Both cell types were stimulated with infected or uninfected DC, as well as supernatant from these DC in an ELISPOT format.
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cells were the most frequent producers of IL-17 in response to cultured supernatant (Fig. 6B), even at 4 wk postinfection. Although there were IL-17-producing CD4 T cells, the frequency was low (Fig. 6B).
At 4 wk postinfection in the lung, the frequency of IL-17-producing cells in the subset was much higher than in the CD4+ T cell subset (Fig. 6C). The proportion of cells, expressed as a percentage of CD3+ cells, ranged between 2 and 3% in the lung throughout infection, whereas CD4 cells were between 47 and 54% of CD3+ cells (Fig. 6D). When the differing proportion of these cell types was taken into account, cells remained the dominant producers of IL-17 (Fig. 6E). The induction of IL-17 by infected DC supernatant was unaffected by the absence of IL-12 p35 but was ablated by the absence of IL-12/IL-23 p40, confirming a requirement for IL-23 (data not shown).
No IFN- production could be detected by cells from spleen or lung (in ELISPOT) at 2 wk postinfection, which is consistent with the kinetics of the T cell response to low dose M. tuberculosis infection (14). However, in contrast to IL-17 production, IFN- production at 4 wk postinfection in the lung and spleen was dominated by CD4+ cells (data not shown). This is consistent with initial IL-17 production before significant T cell priming and IFN- production. In contrast to IL-17 production by cells, production of IFN- by CD4+ T cells required M. tuberculosis-infected DC (data not shown).
FACS analysis confirmed the ELISPOT findings. Lung cells from naive mice and mice 8 wk postinfection were stimulated with ionomycin and PMA, and IL-17 was detected by intracellular cytokine staining. The percentage of IL-17-positive cells was greater than CD4 T cells at both time points (Fig. 7). CD4 T cell staining for IFN- is increased in infected mice compared with naive mice (data not shown). In contrast, CD4 T cell staining for IL-17 remained low throughout the course of infection (Fig. 7).
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Discussion |
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T cells, dominate the early production of IL-17 in response to IL-23 in M. tuberculosis infection, and these cells continue to produce this cytokine throughout the infection. We also demonstrate that naive T cells are major producers of IL-17 in response to IL-23. This supports an innate response for T cells in stimulating inflammation in response to bacterial infection.
In analyzing the IL-17 expression in the lung during infection, we found anti-CD3/CD28 Ab stimulation to be a poor inducer of IL-17 compared with stimulation with ionomycin/PMA (data not shown). Supernatant from M. tuberculosis-infected DC or IL-23 alone could induce IL-17 in cells. This suggested that TCR engagement could be bypassed and appears to be insufficient for IL-17 secretion. In contrast, anti-CD3/CD28 Ab is a strong inducer of IFN- from these lung cells, although primarily from CD4 T cells.
Production of IL-17 by T cells in response to IL-23 appears to be an innate response, because this subset from naive mice responded with substantial IL-17 production when stimulated with infected DC, supernatant from infected DC, or rIL-23. The ratio of to CD4 cells in naive mice remained similar throughout the course of infection. At the earliest time points examined, there was no IFN- produced in the lungs, but substantial IL-17, indicating that this is an early event in infection. The IL-17 production may be important for initiating early inflammatory events. At later time points, IL-17 production from CD4 T cells increased, and both subsets contributed to the total amount of IL-17 in the lungs.
The role of IL-17 in M. tuberculosis infection, either beneficial or detrimental, is not yet clear. At least in the mouse model, IL-23 is not required for control of this infection, nor is it necessary for IFN- production in the presence of IL-12 (16). However, the use of M. tuberculosis as a model system allows one to observe the cell subsets that can produce this cytokine, perhaps in part because of the slow induction of an IFN--producing subset of T cells. It has been demonstrated that IFN- inhibits development of the Th17 cells (4, 5), and there is little IFN- present in the lungs during the initial 2 wk of infection with M. tuberculosis. The effects of IFN- on IL-17 production by T cells are not known. Therefore, the lung environment early in infection is conducive to IL-17 production. Even after CD4 T cell priming and substantive production of IFN-, we found T cell (and other non-CD4+ T cell) production of IL-17, and the contribution from cells was consistently greater than that from the CD4 T cells. After T cell priming, the immune response is characterized by a strong IFN- response; this may explain the relatively weak (compared with IFN-) IL-17 response from CD4+ T cells. Therefore, during an immune response dominated by IFN- (or perhaps even IL-4), cells may assume a more dominant role in producing IL-17.
How might early induction of IL-17 contribute to the immune response against lung pathogens, including M. tuberculosis? IL-23 induction of IL-17 from lung cells has recently been implicated in steady-state granulopoiesis, which balances influx and apoptosis of neutrophils in the lung (17). We propose that this feedback mechanism between lung APCs and cells acts as a proinflammatory network during infection. Neutrophils are found in the tuberculous granulomas of mice, humans, and nonhuman primates. The role of neutrophils in granuloma formation and lung inflammation in M. tuberculosis is not well understood. There is also an accumulation of cells in the lungs of mice infected with the tuberculosis vaccine strain BCG at day 7, before that of Ag-specific T cells at 3 wk (9). KO mice infected with M. tuberculosis did not demonstrate differences in bacterial load compared with wild-type mice, although granuloma structure was less organized (12, 24). At higher infectious doses, there was extensive influx of neutrophils and foamy macrophages in the KO mice (12, 24). A general early proinflammatory role during infection and a late anti-inflammatory role for cells during infections has been proposed (25).
Activation of resting V1 T cells is mediated by soluble factors from BCG-infected DC (26). These factors cause T cells to up-regulate CD69 expression, and enhance cytotoxicity and DC IL-12 production by secretion of IFN-. The IFN- production was most likely IL-12p70 mediated; however, we found only low-level IL-12p70 production from M. tuberculosis-infected DC.
Our results are consistent with a role for cells as early responders that promote inflammation by production of IL-17. These cells do so before CD4 T cell priming (and IFN- production). It has been suggested that the early expression of cytokines by cells may fit the Th1/Th2 paradigm, implying a role in influencing CD4 T cell development. Early in the course of Listeria monocytogenes infection, cells express IFN-, whereas early in Nippostrongylus brasiliensis infection, cells express IL-4 (27). We show here that cells produce IL-17 early in infection, thereby mirroring the recent incorporation of Th17 cells to the paradigm. In this case, the IL-17 most likely promotes an influx of cells to the lungs, although a direct role for influencing CD4 T cell development may emerge in M. tuberculosis infection. It is interesting to note that this IL-17 production coexists with CD4 T cell production of IFN- at later stages of infection.
It has also recently been shown that activated T cells can present Ag to CD4 cells in a model of alternative Ag presentation function (28, 29). It is tempting to speculate that, early in infection, cells are activated in the lung by mycobacterial Ag and cytokines such as IL-23. These activated cells then in turn produce IL-17 aiding inflammation and up-regulate surface costimulatory molecules and MHC class II to facilitate Ag presentation to subsequently infiltrating T cells.
The data presented in this study demonstrate that, in addition to the newly recognized Th17 CD4 T cell subset, T cells as well as other non-CD4/CD8 cells can produce IL-17 in response to factors, including IL-23, produced by M. tuberculosis-infected DC. These cells, present in naive mice as well as M. tuberculosis-infected mice, may play an important role in initiating inflammation and recruiting cells to the site of infection. There may be additional roles for IL-17-secreting cells during infections that are specific to these non-classically restricted T cells.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This work was supported by National Institutes of Health Grants RO1 AI50732 and AI37859 (to J.L.F.), T32 CA82084-07 (to E.L.), and AI060525 (to A.M.G.) and C Advisors Grant. 
2 Address correspondence and reprint requests to Dr. JoAnne L. Flynn, W1157 Biomedical Science Tower, Pittsburgh, PA 15261. E-mail address: joanne{at}pitt.edu
3 Abbreviations used in this paper: BCG, bacillus Calmette-Guérin; KO, knockout; DC, dendritic cell.
Received for publication April 26, 2006. Accepted for publication July 14, 2006.
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K. Shibata, H. Yamada, R. Nakamura, X. Sun, M. Itsumi, and Y. Yoshikai Identification of CD25+ {gamma}{delta} T Cells As Fetal Thymus-Derived Naturally Occurring IL-17 Producers J. Immunol., November 1, 2008; 181(9): 5940 - 5947. [Abstract] [Full Text] [PDF]
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J. M. W. Quinn, N. A. Sims, H. Saleh, D. Mirosa, K. Thompson, S. Bouralexis, E. C. Walker, T. J. Martin, and M. T. Gillespie IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice J. Immunol., October 15, 2008; 181(8): 5720 - 5729. [Abstract] [Full Text] [PDF]
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 M. N. Ajuebor, Y. Jin, G. L. Gremillion, R. M. Strieter, Q. Chen, and P. A. Adegboyega {gamma}{delta}T Cells Initiate Acute Inflammation and Injury in Adenovirus-Infected Liver via Cytokine-Chemokine Cross Talk J. Virol., October 1, 2008; 82(19): 9564 - 9576. [Abstract] [Full Text] [PDF]
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S. Hamada, M. Umemura, T. Shiono, K. Tanaka, A. Yahagi, M. D. Begum, K. Oshiro, Y. Okamoto, H. Watanabe, K. Kawakami, et al. IL-17A Produced by {gamma}{delta} T Cells Plays a Critical Role in Innate Immunity against Listeria monocytogenes Infection in the Liver J. Immunol., September 1, 2008; 181(5): 3456 - 3463. [Abstract] [Full Text] [PDF]
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S. M. Schulz, G. Kohler, C. Holscher, Y. Iwakura, and G. Alber IL-17A is produced by Th17, {gamma}{delta} T cells and other CD4- lymphocytes during infection with Salmonella enterica serovar Enteritidis and has a mild effect in bacterial clearance Int. Immunol., September 1, 2008; 20(9): 1129 - 1138. [Abstract] [Full Text] [PDF]
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N. Takahashi, I. Vanlaere, R. de Rycke, A. Cauwels, L. A.B Joosten, E. Lubberts, W. B. van den Berg, and C. Libert IL-17 produced by Paneth cells drives TNF-induced shock J. Exp. Med., August 4, 2008; 205(8): 1755 - 1761. [Abstract] [Full Text] [PDF]
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J. R. Lees, Y. Iwakura, and J. H. Russell Host T Cells Are the Main Producers of IL-17 within the Central Nervous System during Initiation of Experimental Autoimmune Encephalomyelitis Induced by Adoptive Transfer of Th1 Cell Lines J. Immunol., June 15, 2008; 180(12): 8066 - 8072. [Abstract] [Full Text] [PDF]
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L. Li and C.-Y. Wu CD4+CD25+ Treg cells inhibit human memory {gamma}{delta} T cells to produce IFN-{gamma} in response to M tuberculosis antigen ESAT-6 Blood, June 15, 2008; 111(12): 5629 - 5636. [Abstract] [Full Text] [PDF]
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M. Lochner, L. Peduto, M. Cherrier, S. Sawa, F. Langa, R. Varona, D. Riethmacher, M. Si-Tahar, J. P. Di Santo, and G. Eberl In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ ROR{gamma}t+ T cells J. Exp. Med., June 9, 2008; 205(6): 1381 - 1393. [Abstract] [Full Text] [PDF]
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 K Dheda, J-S Chang, S Lala, J F Huggett, A Zumla, and G A W Rook Gene expression of IL17 and IL23 in the lungs of patients with active tuberculosis Thorax, June 1, 2008; 63(6): 566 - 568. [Full Text] [PDF]
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X. O. Yang, S. H. Chang, H. Park, R. Nurieva, B. Shah, L. Acero, Y.-H. Wang, K. S. Schluns, R. R. Broaddus, Z. Zhu, et al. Regulation of inflammatory responses by IL-17F J. Exp. Med., May 12, 2008; 205(5): 1063 - 1075. [Abstract] [Full Text] [PDF]
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L. Romani, T. Zelante, A. De Luca, F. Fallarino, and P. Puccetti IL-17 and Therapeutic Kynurenines in Pathogenic Inflammation to Fungi J. Immunol., April 15, 2008; 180(8): 5157 - 5162. [Abstract] [Full Text] [PDF]
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T. J. Scriba, B. Kalsdorf, D.-A. Abrahams, F. Isaacs, J. Hofmeister, G. Black, H. Y. Hassan, R. J. Wilkinson, G. Walzl, S. J. Gelderbloem, et al. Distinct, Specific IL-17- and IL-22-Producing CD4+ T Cell Subsets Contribute to the Human Anti-Mycobacterial Immune Response J. Immunol., February 1, 2008; 180(3): 1962 - 1970. [Abstract] [Full Text] [PDF]
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E. Smith, A. Zarbock, M. A. Stark, T. L. Burcin, A. C. Bruce, P. Foley, and K. Ley IL-23 Is Required for Neutrophil Homeostasis in Normal and Neutrophilic Mice J. Immunol., December 15, 2007; 179(12): 8274 - 8279. [Abstract] [Full Text] [PDF]
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C. L. Roark, J. D. French, M. A. Taylor, A. M. Bendele, W. K. Born, and R. L. O'Brien Exacerbation of Collagen-Induced Arthritis by Oligoclonal, IL-17-Producing {gamma}{delta} T Cells J. Immunol., October 15, 2007; 179(8): 5576 - 5583. [Abstract] [Full Text] [PDF]
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 A. Linden A Role for the Cytoplasmic Adaptor Protein Act1 in Mediating IL-17 Signaling Sci. Signal., August 7, 2007; 2007(398): re4 - re4. [Abstract] [Full Text] [PDF]
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W. Sato, T. Aranami, and T. Yamamura Cutting Edge: Human Th17 Cells Are Identified as Bearing CCR2+CCR5- Phenotype J. Immunol., June 15, 2007; 178(12): 7525 - 7529. [Abstract] [Full Text] [PDF]
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A. Maitra, F. Shen, W. Hanel, K. Mossman, J. Tocker, D. Swart, and S. L. Gaffen Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression PNAS, May 1, 2007; 104(18): 7506 - 7511. [Abstract] [Full Text] [PDF]
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