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Coexistent helminth infections are known to modulate T cell and cytokine responses in latent infection with Mycobacterium tuberculosis. However, their role in modulating chemokine responses in latent tuberculosis (LTB) has not been explored. Because chemokines play a vital role in the protective immune responses in LTB, we postulated that coexistent helminth infection could modulate chemokine production in helminth-LTB coinfection. To test this, we measured the levels of a panel of CC and CXC chemokines at baseline and following mycobacterial Ag or mitogen stimulation in individuals with LTB with (Strongyloides stercoralis+LTB+) or without S. stercoralis (S. stercoralis−LTB+) infection and in individuals without both infections, healthy controls (HC). At baseline (in the absence of a stimulus), S. stercoralis+LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL9, CXCL10, and CXCL11 in comparison with S. stercoralis−LTB+ and/or HC individuals. Upon mycobacterial Ag stimulation, S. stercoralis+LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL2, CXCL9, and CXCL10 in comparison with S. stercoralis−LTB+ and/or HC individuals. No differences were observed upon mitogen stimulation. Finally, after anthelmintic treatment, the baseline levels of CCL1, CCL2, CCL4, CCL11, and CXCL11 and mycobacterial Ag–stimulated levels of CCL1, CCL2, CCL11, CXCL2, and CXCL10 were significantly increased in S. stercoralis+LTB+ individuals. Thus, our data demonstrate that S. stercoralis+LTB+ individuals are associated with a compromised ability to express both CC and CXC chemokines and that this defect is at least partially reversible upon treatment. Hence, coexistent helminth infection induces downmodulation of chemokine responses in LTB individuals with likely potential effects on tuberculosis pathogenesis.

Background Human and animal studies have demonstrated that helminth infections are associated with a decreased prevalence of type 2 diabetes mellitus (T2DM). However, very little is known about their biochemical and immunological interactions. Methods To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss), and T2DM, we examined analytes associated with glycemic control, metabolic processes, and T-cell–driven inflammation at the time of Ss diagnosis and 6 months after definitive anthelmintic treatment. We measured plasma levels of hemoglobin A1c, glucose, insulin, glucagon, adipocytokines, and T-helper (TH) 1-, 2-, and 17- associated cytokines in patients with T2DM with (INF group) or without (UN group) Ss infection. In INF individuals, we again assessed the levels of these analytes 6 months following anthelmintic treatment. Results Compared to UN individuals, INF individuals exhibited significantly diminished levels of insulin and glucagon that increased significantly following therapy. Similarly, INF individuals exhibited significantly diminished levels of adiponectin and adipsin that reversed following therapy. INF individuals also exhibited significantly decreased levels of the TH1- and TH17- associated cytokines in comparison to UN individuals; again, anthelmintic therapy augmented these levels. As expected, INF individuals had elevated levels of TH2-associated and regulatory cytokines that normalized following definitive therapy. Multivariate analysis revealed that these changes were independent of age, sex, body mass index, and liver and renal function. Conclusions Strongyloides stercoralis infection is associated with a significant modulation of glycemic, hormonal, and cytokine parameters in T2DM and its reversal following anthelmintic therapy. Hence, Ss infection has a protective effect on diabetes-related parameters.

High body mass index (HBMI) has been shown to be protective against active tuberculosis (TB), although the biological mechanism underlying this protection is poorly understood. The immunological association between HBMI and latent TB has never been examined. In order to study the association of HBMI with latent TB, we examined the circulating and TB- antigen or mitogen stimulated levels of a large panel of cytokines in individuals with latent TB (LTB) and high or normal body mass index (HBMI or NBMI). HBMI is characterized by heightened circulating levels of pro-inflammatory (IFNγ, TNFα, IL-22, IL-1α, IL-12 and GM-CSF) cytokines but decreased circulating levels of anti-inflammatory cytokines (IL-4, IL-5 and TGFβ). This systemic cytokine profile is associated with elevated TB-antigen and mitogen stimulated levels of IFNγ, TNFα, IL-2 and IL-1α and diminished levels of IL-10 and TGFβ. In addition, we also observed a positive correlation between the circulating levels of IFNγ, TNFα, IL-22, IL-1α with BMI and a negative correlation between the circulating levels of IL-10, TGFβ and BMI. Our data, therefore, suggest the modulation of protective and regulatory cytokines might underlie the protective effect of HBMI against the development of active TB.

Strongyloides stercoralis is a soil-transmitted helminth organism that infects ∼50 to 100 million people worldwide. Despite its widespread prevalence, very little is known about the immune response that characterizes human S. stercoralis infection. To study the systemic cytokine profile characteristic of Strongyloides infection, we measured the circulating levels of a large panel of pro- and anti-inflammatory cytokines in asymptomatic, infected individuals ( n = 32) and compared them to those in uninfected, controls ( n = 24). Infected individuals exhibited significantly lower circulating levels of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-1β [IL-1β]) and significantly higher levels of anti-inflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and transforming growth factor β [TGF-β]). Moreover, treatment of Strongyloides infection resulted in a significant reversal of the cytokine profile, with increased levels of proinflammatory (IFN-γ, TNF-α, IL-2, IL-17A, IL-17F, IL-22, IL-23, and IL-1β) and decreased levels of anti-inflammatory (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-β) cytokines following treatment. Thus, S. stercoralis infection is characterized by alterations in the levels of systemic cytokines, reflecting major alterations in the underlying immune response to this chronic helminth infection.

Alteration in the frequency of monocyte subsets is a hallmark of tuberculosis–diabetes co‐morbidity (TB‐DM). To study this association, we examined the plasma levels of sCD14, sCD163, C‐reactive protein (CRP) and soluble tissue factor (sTF) in individuals with TB‐DM, TB or diabetes mellitus (DM), and in healthy controls (HC). Circulating levels of sCD14, sCD163 and sTF were significantly increased in TB‐DM and DM compared with TB and HC; however, CRP was significantly increased in TB‐DM and TB compared with DM and HC. During longitudinal follow up, sCD14, CRP and sTF levels remained significantly increased in TB‐DM compared with TB from baseline (pre‐treatment), during treatment (2nd month) and at the completion (6th month) of anti‐TB treatment (ATT), whereas sCD163 was significantly higher in TB‐DM compared with TB only at baseline. Moreover, the levels of sCD14 and sCD163 were significantly higher in TB‐DM individuals with bilateral and cavitary disease and exhibited a significant positive relationship with bacterial burden. Levels of sCD14, sCD163 and CRP exhibited a positive relationship with HbA1c levels. Within the TB‐DM group, those with known diabetes before incident TB (KDM) exhibited significantly higher levels of sCD14 and sCD163 compared with individuals with newly diagnosed DM with TB (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of sCD14, sCD163 and CRP compared with those on non‐metformin‐containing regimens. Our data demonstrate that systemic monocyte activation marker levels reflect baseline disease severity and extent in TB‐DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy.

Type III IFNs are important players in immunity to viral and bacterial infections. However, their association with helminth infections has not been examined. To explore the association of Type III IFNs with Strongyloides stercoralis (Ss) infection, we examined the systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in Ss infected (INF, n = 44), helminth-uninfected (UN, n = 44) and in post-treatment INF individuals. We also examined the levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in whole blood culture supernatants stimulated with Ss somatic antigens, or PPD or LPS. Finally, we performed correlations of systemic Type III IFN levels with absolute numbers of dendritic cell subsets. Ss infection is characterized by elevated systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in comparison to UN individuals and a significant reduction following anthelmintic treatment. Ss infection is also characterized by elevated levels of unstimulated or Ss antigen stimulated levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, CXCL10/IP-10 and a significant reduction following treatment. In addition, Ss infection is characterized by increased numbers of plasmacytoid and myeloid dendritic cells in comparison to UN individuals, with a significant reduction following anthelmintic treatment of INF individuals. Finally, Ss infection exhibits a significant positive correlation between the systemic levels of IFN lambda-2 and IFN lambda-3 and the numbers of plasmacytoid dendritic cells. Thus, Ss infection is characterized by elevations in systemic and antigen-induced levels of Type III IFNs, which is positively associated with the numbers of plasmacytoid dendritic cells and reversed upon anthelmintic treatment.

Summary Objectives Previous studies have demonstrated a diminution in the baseline and mycobacterial antigen – specific cytokines in low body mass index (LBMI) individuals with latent tuberculosis infection (LTBI). We hypothesized that LBMI might be also associated with alteration in the baseline and antigen – stimulated levels of chemokines in LTBI. Methods To test this hypothesis, we examined baseline, TB-antigen and mitogen stimulated levels of chemokines in these individuals and compared them with those with LTBI and normal BMI (NBMI). Results LBMI with LTBI is characterized by diminished baseline levels of CCL1, CCL4, CCL11, CXCL1, CXCL9, CXCL10 and CXCL11 in comparison to NBMI with LTBI. Similarly, LTBI with LBMI is also characterized by diminished TB-antigen stimulated levels of CCL1, CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL9, CXCL10 and CXCL11. In contrast, there were no significant differences in the mitogen stimulated chemokine levels between the groups. Finally, there was a significant positive correlation between BMI and CCL1, CCL4, CCL11, CXCL11, CXCL2, CXCL9 and CXCL11 levels in LTBI individuals. Conclusions Therefore, our data reveal that LTBI subjects with low BMI are characterized by diminished levels of a variety of important chemokines, providing a novel biological mechanism for the increased risk of developing active TB.

Strongyloides stercoralis infection is associated with diminished antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4 + and CD8 + T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis -infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.

Infection with the helminth parasite Strongyloides stercoralis (Ss) is commonly clinically asymptomatic that is often accompanied by peripheral eosinophilia. Granulocytes are activated during helminth infection and can act as immune effector cells. Plasma levels of eosinophil and neutrophil granular proteins convey an indirect measure of granulocyte degranulation and are prominently augmented in numerous helminth-infected patients. In this study, we sought to examine the levels of eosinophil, neutrophil, and mast cell activation-associated granule proteins in asymptomatic Ss infection and to understand their kinetics following anthelmintic therapy. To this end, we measured the plasma levels of eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil major basic protein, neutrophil elastase, myeloperoxidase, neutrophil proteinase-3, mast cell tryptase, leukotriene C4, and mast cell carboxypeptidase-A3 in individuals with asymptomatic Ss infection or without Ss infection [uninfected (UN)]. We also estimated the levels of all of these analytes in infected individuals following definitive treatment of Ss infection. We demonstrated that those infected individuals have significantly enhanced plasma levels of eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil major basic protein, elastase, myeloperoxidase, mast cell tryptase, leukotriene C4, and carboxypeptidase-A3 compared to UN individuals. Following the treatment of Ss infection, each of these granulocyte-associated proteins drops significantly. Our data suggest that eosinophil, neutrophil, and mast cell activation may play a role in the response to Ss infection.

Strongyloides stercoralis infection is associated with diminished antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.

Helminth infections are known to modulate cytokine responses in latent tuberculosis (LTB). However, very few studies have examined whether this modulation is reversible upon anthelmintic therapy. We measured the systemic and mycobacterial (TB) antigen-stimulated levels of type 1, type 2, type 17, and regulatory cytokines in individuals with LTB and with or without coexistent Strongyloides stercoralis infection before and after anthelmintic therapy. Our data reveal that individuals with LTB and coexistent S. stercoralis infection have significantly lower levels of systemic and TB antigen-stimulated type 1 (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and type 17 (IL-17A and/or IL-17F) cytokines and significantly higher levels of systemic but not TB antigen-stimulated type 2 (IL-4 and IL-5) and regulatory (transforming growth factor beta [TGF-β]) cytokines. Anthelmintic therapy resulted in significantly increased systemic levels of type 1 and/or type 17 cytokines and in significantly decreased systemic levels of type 2 and regulatory (IL-10 and TGF-β) cytokines. In addition, anthelmintic therapy resulted in significantly increased TB antigen-stimulated levels of type 1 cytokines only. Our data therefore confirm that the modulation of systemic and TB antigen-stimulated cytokine responses in S. stercoralis -LTB coinfection is reversible (for the most part) by anthelmintic treatment.

Background / Objectives Helminth infections are known to influence T cell responses in latent tuberculosis (LTBI). Whether helminth infections also modulate B cell responses in helminth-tuberculosis co-infection is not known. Methods We assessed Mycobacterium tuberculosis (Mtb)–antigen specific IgM and IgG levels, circulating levels of the B cell growth factors, BAFF and APRIL and the absolute numbers of the various B cell subsets in individuals with LTBI, LTBI with coincident Strongyloides stercoralis (Ss) infection (LTBI/Ss) and in those with Ss infection alone (Ss). We also measured the above-mentioned parameters in the LTBI-Ss group after anthelmintic therapy. Results Our data reveal that LTBI-Ss exhibit significantly diminished levels of Mtb-specific IgM and IgG, BAFF and APRIL levels in comparison to those with LTBI. Similarly, those with LTBI-Ss had significantly diminished numbers of all B cell subsets (naïve, immature, classical memory, activated memory, atypical memory and plasma cells) compared to those with LTBI. There was a positive correlation between Mtb—antigen specific IgM and IgG levels and BAFF and APRIL levels that were in turn related to the numbers of activated memory B cells, atypical memory B cells and plasma cells. Finally, anthelmintic treatment resulted in significantly increased levels of Mtb—antigen specific IgM and IgG levels and the numbers of each of the B cell subsets. Conclusions Our data, therefore, reveal that Ss infection is associated with significant modulation of Mtb-specific antibody responses, the levels of B cell growth factors and the numbers of B cells (and their component subsets)., Author summary Helminth infections and tuberculosis are two of the major health care problems worldwide and share a great deal of geographical overlap. Moreover, helminth infections are known to induce immune responses that are antagonistic to the protective immune responses elicited by Mycobacterium tuberculosis. Having previously demonstrated that helminth infections can profoundly alter protective T cell responses needed to control tuberculosis infection, we examined how Strongyloides stercoralis (Ss) infection influences B cell responses in latent tuberculosis infection (LTBI) in the context of co-infection and showed the Ss infection is associated with dramatic alterations in mycobacterial-specific IgG and IgM responses and levels of B cells and their growth factors BAFF and APRIL. These alterations in B cell responses could have implications for vaccine-induced immune responses to tuberculosis in helminth—endemic countries.

Microbial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic Strongyloides stercoralis infection, we measured the plasma levels of LPS and other microbial translocation markers, acute-phase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN]) S. stercoralis infections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of S. stercoralis infection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (α-2 macroglobulin [α-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1β) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of S. stercoralis infection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that S. stercoralis infection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic S. stercoralis infection and is associated with an inflammatory response.

Background CD4+ and CD8+ T cells are central players in immunity to helminth infections. However, the role of T cell subsets in human helminth infections is not well understood. In addition, the common γc cytokines, IL-2, IL-4, IL-7, IL-9 and IL-15 play an important role in the maintenance of these CD4+ and CD8+ T cell subsets. Methods To examine the major T cell subsets and their association with the common γc cytokines, the absolute numbers of CD4+ and CD8+ naïve, central memory, effector memory and effector cells and the plasma levels of IL-2, IL-4, IL-7, IL-9 and IL-15 were measured in Strongyloides stercoralis (Ss) infected (INF, n = 60), helminth—uninfected (UN, n = 58) and in post treatment INF individuals. Results Ss infection is characterized by significantly increased absolute numbers of naïve and decreased absolute numbers of central and effector memory CD4+ T cells in comparison to UN individuals. No significant difference in the numbers of CD8+ T cell subsets was observed between the groups. The numbers of naïve cells and central memory CD4+ T cells were significantly reversed after anthelmintic treatment. Circulating levels of IL-2, IL-7 and IL-15 were significantly diminished, whereas the levels of IL-4 and IL-9 were significantly increased in INF compared to UN individuals. Following anthelminthic treatment, IL-2, IL-7 and IL-15 levels were significantly increased, while IL-4 and IL-9 levels were significantly decreased. Our data also showed a significant positive correlation between the levels of IL-7 and the numbers of central and effector memory CD4+ T cells. Conclusion Ss infection is characterized by alterations in the absolute numbers of CD4+ T cell subsets and altered levels of common γc cytokines IL-2, IL-4, IL-7, IL-9 and IL-15; alterations which are partially reversed after anthelmintic treatment., Author summary Strongyloides stercoralis (Ss), an intestinal nematode, the causative agent of strongyloidiasis, infects 30–100 million people worldwide. Ss infection is often clinically asymptomatic and long lasting due, in large part, to the parasites auto-infective life cycle and their ability to modulate the host immune system. Th1 cells are down modulated and Th2 cells are essential for fighting against helminth infections. T cells proliferate in response to common γc dependent cytokine signaling. The role of CD4+ and CD8+ T cell subset distribution and the association between memory T cell subsets and the common γc cytokines (IL-2, IL-4, IL-7, IL-9 and IL-15) in helminth infections has not been explored well. We examined the ex-vivo phenotypic profile of CD4+ and CD8+ T cell subsets and the circulating levels of common γc cytokines in Ss-infected, uninfected and post treatment individuals. Ss infected individuals showed alterations in the T cell subset distribution and these alterations were partially reversed following anthelminthic treatment. This was associated with altered plasma levels of IL-2, IL-4, IL-7, IL-9 and IL-15 and partial reversal following anthelminthic treatment. IL-7 exhibited significant positive association with central and effector memory CD4+ T cells. Our study would provide stimulus to examine further about the function of T cell subset distribution and the role and association of common γc cytokines with parasitic infections.

Malnutrition, as defined by low body mass index (BMI), is a major risk factor for the development of active tuberculosis (TB), although the biological basis underlying this susceptibility remains poorly characterized. To verify whether malnutrition affects the systemic and antigen-specific cytokine levels in individuals with latent TB (LTB), we examined circulating and TB antigen-stimulated levels of cytokines in individuals with LTB and low BMI (LBMI) and compared them with those in individuals with LTB and normal BMI (NBMI). Coexistent LBMI with LTB was characterized by diminished circulating levels of type 1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), type 2 (interleukin-4 [IL-4]), type 17 (IL-22), and other proinflammatory (IL-1α, IL-1β, and IL-6) cytokines but elevated levels of other type 2 (IL-5 and IL-13) and regulatory (IL-10 and transforming growth factor beta [TGF-β]) cytokines. In addition, LBMI with LTB was associated with diminished TB antigen-induced IFN-γ, TNF-α, IL-6, IL-1α, and IL-1β levels. Finally, there was a significant positive correlation between BMI values and TNF-α and IL-1β levels and a significant negative correlation between BMI values and IL-2, IL-10, and TGF-β levels in individuals with LTB. Therefore, our data reveal that latent TB with a coexistent low BMI is characterized by diminished protective cytokine responses and heightened regulatory cytokine responses, providing a potential biological mechanism for the increased risk of developing active TB.

Background Th9 cells are a subset of CD4+ T cells that express the protoypical cytokine, IL-9. Th9 cells are known to effect protective immunity in animal models of intestinal helminth infections. However, the role of Th9 cells in human intestinal helminth infections has never been examined. Methodology To examine the role of Th9 cells in Strongyloidis stercoralis (Ss), a common intestinal helminth infection, we compared the frequency of Th9 expressing IL-9 either singly (mono-functional) or co-expressing IL-4 or IL-10 (dual-functional) in Ss-infected individuals (INF) to frequencies in uninfected (UN) individuals. Principal Findings INF individuals exhibited a significant increase in the spontaneously expressed and/or antigen specific frequencies of both mono- and dual-functional Th9 cells as well as Th2 cells expressing IL-9 compared to UN. The differences in Th9 induction between INF and UN individuals was predominantly antigen-specific as the differences were no longer seen following control antigen or mitogen stimulation. In addition, the increased frequency of Th9 cells in response to parasite antigens was dependent on IL-10 and TGFx since neutralization of either of these cytokines resulted in diminished Th9 frequencies. Finally, following successful treatment of Ss infection, the frequencies of antigen-specific Th9 cells diminished in INF individuals, suggesting a role for the Th9 response in active Ss infection. Moreover, IL-9 levels in whole blood culture supernatants following Ss antigen stimulation were higher in INF compared to UN individuals. Conclusion Thus, Ss infection is characterized by an IL-10- and TGFβ dependent expansion of Th9 cells, an expansion found to reversible by anti-helmintic treatment., Author Summary Strongyloides stercoralis is a common intestinal parasite affecting about 50–100 million people worldwide. It is characterized by a complex lifecycle involving both free- living and parasitic stages and the clinical manifestations range from asymptomatic infection to multi-organ failure. It has the propensity to cause disseminated disease and death in immunocompromised individuals. Therefore, an in depth understanding of the immune responses to this helminth parasite is warranted. However, what we know about the immunity to this infection is mostly derived from animal studies. Th9 cells are a subset of CD4+ T cells producing the cytokine—IL-9. Since Th9 cells are increasingly recognized as being important in immunity to intestinal infection with helminths, we examined the induction and regulation Th9 cell responses to Ss infection utilizing infected and uninfected individuals from an endemic area in India. We show that Ss infection is characterized by profound alterations in the Th9 compartment and that this response is mainly regulated by the cytokines—IL-10 and TGFβ. In addition, we also demonstrate that active infection is a pre-requisite for this regulation and anti-Ss treatment can dampen enhanced Th9 responses.