Distinct types of CD4(+) T cells protect the host against different classes of pathogens. However, it is unclear whether a given pathogen induces a single type of polarized T cell. By combining antigenic stimulation and T cell receptor deep sequencing, we found that human pathogen- and vaccine-specific T helper 1 (T(H)1), T(H)2, and T(H)17 memory cells have different frequencies but comparable diversity and comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates. Single naïve T cells primed by a pathogen in vitro could also give rise to multiple fates. Our results unravel an unexpected degree of interclonal and intraclonal functional heterogeneity of the human T cell response and suggest that polarized responses result from preferential expansion rather than priming.

Graphical Abstract Highlights d The skin commensal yeast Malassezia drives type 17 immunity in the skin d Malassezia-specific human memory T cells display a Th17 phenotype d Mice deficient in IL-17AF or IL-23 show uncontrolled Malassezia growth on the skin d In the disrupted skin, IL-23 and IL-17AF promote Malasseziainduced inflammation SUMMARY Commensal fungi of the mammalian skin, such as those of the genus Malassezia, are associated with atopic dermatitis and other common inflammatory skin disorders. Understanding of the causative relationship between fungal commensalism and disease manifestation remains incomplete. By developing a murine epicutaneous infection model, we found Malassezia spp. selectively induce IL-17 and related cytokines.This response is key in preventing fungal overgrowth on the skin, as disruption of the IL-23-IL-17 axis compromises Malassezia-specific cutaneous immunity. Under conditions of impaired skin integrity, mimicking a hallmark of atopic dermatitis, the presence of Malassezia dramatically aggravates cutaneous inflammation, which again was IL-23 and IL-17 dependent. Consistently, we found a CCR6 + Th17 subset of memory T cells to be Malassezia specific in both healthy individuals and atopic dermatitis patients, whereby the latter showed enhanced frequency of these cells. Thus, the Malassezia-induced type 17 response is pivotal in orchestrating antifungal immunity and in actively promoting skin inflammation.

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Chitinase 3-like protein 1 (CHI3L-1) and chitotriosidase (CHIT-1) are members of the chitinase family. CHI3L-1 is a newly recognized protein that is secreted by activated macrophages and neutrophils and expressed in a broad spectrum of inflammatory conditions and cancers. In human plasma, CHIT-1 activity has been proposed as a biochemical marker of macrophage activation. Although CHI3L-1 expression in inflammation is under examination, little is known regarding its regulation during macrophages' full maturation and polarization. In this study, we compared CHI3L-1 and CHIT-1 modulation during monocyte to macrophage transition and polarization. Gene expression analysis was investigated by real-time PCR. We found that during the maturation of monocytes into macrophages, the expression of both CHI3L-1 and CHIT-1 increased exponentially over time. Additionally, we observed a different regulation of CHI3L-1 and CHIT-1 in undifferentiated monocytes under stimulation with lipopolysaccharide, interferon-γ, and interleukin-4, at the same concentration used to polarize macrophages. Our finding suggests that in the immune response, the role of CHI3L-1 and CHIT-1 is not restricted to innate immunity, but they are also protagonists in acquired immunity.

Macrophages as a principal component of immune system play an important role in the initiation, modulation, and final activation of the immune response against pathogens. Upon stimulation with different cytokines, macrophages can undergo classical or alternative activation to become M1 or M2 macrophages, which have different functions during infections. Although chitotriosidase is widely accepted as a marker of activated macrophages and is thought to participate in innate immunity, particularly in defense mechanisms against chitin containing pathogens, little is known about its expression during macrophages full maturation and polarization. In this study we analyzed CHIT-1 modulation during monocyte-to-macrophage maturation and during their polarization. The levels of CHIT-1 expression was investigated in human monocytes obtained from buffy coat of healthy volunteers, polarized to classically activated macrophages (or M1), whose prototypical activating stimuli are interferon-γ and lipopolysaccharide, and alternatively activated macrophages (or M2) obtained by interleukin-4 exposure by real-time PCR and by Western blot analysis. During monocyte-macrophage differentiation both protein synthesis and mRNA analysis showed that CHIT-1 rises significantly and is modulated in M1 and M2 macrophages.Our results demonstrated that variations of CHIT-1 production are strikingly associated with macrophages polarization, indicating a different rule of this enzyme in the specialized macrophages.

Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT-1) are two active chitinases expressed in humans. The chitinase activity of AMCase was found to be causative in allergic inflammation and its expression was found to be induced by interleukin-13. CHIT1-1 is expressed by phagocytic cells and extremely high levels are seen in lysosomal storage diseases. Despite that AMCase expression in the inflammation is under investigation, little is known regarding its regulation during macrophages' full maturation and polarization. In this study, we compared AMCase and CHIT-1 modulation during monocyte to macrophage transition and polarization. Gene expression analysis was investigated by real-time PCR from mRNA of human monocytes obtained from buffy coat of healthy volunteers, from mRNA of polarized to classically activated macrophages (or M1), obtained by interferon (IFN)-γ and lipopolysaccharide (LPS) treatment, and from mRNA of alternatively activated macrophages (or M2) obtained by interleukin (IL)-4 exposure. Our results showed that the expression of AMCase and CHIT-1 were differently modulated in HMMs at different stage of maturation. The behavior of these two active chitinase suggests that in the immune response their role is complementary.

Our study revealed that monocytes undergoing maturation differentially regulate the expression of several members of HSPs and that distinct patterns of HSP expression characterize the M1 and M2 effector stages of macrophage life.

These findings suggest that a functional polymorphism in the CHIT-1 gene protects against NAFLD progression.