Progress in material design for biomedical applications

Biomaterials that interface with biological systems are used to deliver drugs safely and efficiently; to prevent, detect, and treat disease; to assist the body as it heals; and to engineer functional tissues outside of the body for organ replacement. The field has evolved beyond selecting materials that were originally designed for other applications with a primary focus on properties that enabled restoration of function and mitigation of acute pathology. Biomaterials are now designed rationally with controlled structure and dynamic functionality to integrate with biological complexity and perform tailored, high-level functions in the body. The transition has been from permissive to promoting biomaterials that are no longer bioinert but bioactive. This perspective surveys recent developments in the field of polymeric and soft biomaterials with a specific emphasis on advances in nano- to macroscale control, static to dynamic functionality, and biocomplex materials.National Institutes of Health. National Heart, Lung, and Blood Institute (Ruth L. Kirschstein National Research Service Award (F32HL1220090)

Single-cell analysis pinpoints distinct populations of cytotoxic CD4(+) T cells and an IL-10(+)CD109(+)TH2 cell population in nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic inflammatory process often associated with comorbid asthma. In this study, we analyzed the transcriptomes of single T helper (T-H) cells from nasal polyps of patients with CRSwNP and validated these findings using multiparameter flow cytometry. Polyp tissue contained suppressive T regulatory (T-reg) cells, T(H)2 cells, type 2 innate lymphoid cells, and three transcriptionally distinct subsets of cytotoxic CD4(+) T cells (CD4(+) CTL). GATA3 expression was a feature of polyp T-reg cells, whereas T(H)2 cells highly expressed TCN1, CD200R, and HPGDS and were enriched for genes involved in lipid metabolism. Only a portion of polyp T(H)2 cells expressed the prostaglandin D2 receptor CRTH2, whereas a subpopulation of CD109(+)CRTH2(-) T(H)2 cells expressed mRNA for common inhibitor receptors including LAG3 and TIM3 and produced IL-10. Together, we resolved the complexity of TH cells in patients with CRSwNP, identifying several distinct clusters of CD4(+) CTL and a population of CD109(+)CRTH2(-) T(H)2 cells with putative regulatory potential

PD-1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator-activated receptor-γ.

Innate lymphoid cells (ILCs) can provide early cytokine help against a variety of pathogens in the lungs and gastrointestinal tract. Type 2 ILC (ILC2) are comparable to T helper 2 cells found in the adaptive immune system, which secrete cytokines such as interleukin 5 (IL-5) and IL-13 and have been found to play roles in host defense against helminth infections and in allergic responses. Recent studies have identified that programmed cell death protein 1 (PD-1) and peroxisome proliferator activated receptor-γ (PPAR-γ) are highly expressed by ILC2. We examined whether PD-1 plays a role in ILC2 function and whether there was any connection between PD-1 and PPAR-γ METHODS: To ensure that only innate immune cells were present, ILC2 cells were examined from RAG1-/- and PD-1-/- xRAG1-/- mice under steady-state or following inoculation with IL-33. We also tested ILC2 generated from bone marrow of RAG1-/- and PD-1-/- xRAG1-/- mice for their production of cytokines. These in vitro-derived ILC2 were also exposed to agonist and antagonist of PPAR-γ

Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived

Intestinal helminth infection transforms the CD4⁺ T cell composition of the skin

Intestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, implying effects on host immune responses in distal barrier tissues. We herein show that the skin of C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus contain higher numbers of CD4(+) T cells compared to the skin of uninfected controls. Accumulated CD4(+) T cells were H. polygyrus-specific T(H)2 cells that skewed the skin CD4(+) T cell composition towards a higher T(H)2/T(H)1 ratio which persisted after worm expulsion. Accumulation of T(H)2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4(+) T cells in the blood and mesenteric lymph nodes draining the infected intestine and was abolished by FTY720 treatment during infection, indicating gut-to-skin trafficking of cells. Remarkably, skin T(H)2 accumulation was associated with impaired capacity to initiate IFN-γ recall responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel process for T cell colonisation and worm-mediated immunosuppression in this organ. [Image: see text

PPAR-γ promotes type 2 immune responses in allergy and nematode infection

A hallmark of immunity to worm infections and many allergies is a strong type 2 immune response. This is characterized by the production of cytokines interleukin-5 (IL-5) and IL-13 by adaptive T helper 2 (TH2) cells and/or type 2 innate lymphoid cells. Peroxisome proliferator activated receptor-γ (PPAR-γ) is typically regarded as an anti-inflammatory factor. We report that TH2 cells express high levels of PPAR-γ in response to the allergen house dust mite and after infection with the parasite Heligmosomoides polygyrus Mice lacking PPAR-γ in T cells failed to effectively differentiate into IL-5- and IL-13-secreting cells and, hence, did not develop TH2 cell-associated pathologies, including goblet cell metaplasia and eosinophilia, in response to allergen challenge. Furthermore, these mice could not mount protective immune responses to nematode infection. In addition, mice lacking PPAR-γ in T cells had greatly reduced frequencies of TH2 cells in visceral adipose tissue. Mechanistically, PPAR-γ appeared to promote the expression of the IL-33 receptor on the surface of TH2 cells. These results pinpoint PPAR-γ as a factor that drives type 2 responses in allergy, worm infection, and visceral adipose tissue

Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity.

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived

Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.</p