Cutting Edge: Influenza-Induced CD11alo Airway CD103+ Tissue Resident Memory T Cells Exhibit Compromised IFN-γ Production after In Vivo TCR Stimulation.

Although tissue resident memory T cells (TRM) in the lung confer robust protection against secondary influenza infection, their in vivo production of IFN-γ is unknown. In this study, using a mouse model, we evaluated production of IFN-γ by influenza-induced TRM (defined as CD103+) that localize to the airways or lung parenchyma. Airway TRM consist of both CD11ahi and CD11alo populations, with low CD11a expression signifying prolonged airway residence. In vitro, high-dose peptide stimulation evoked IFN-γ from most CD11ahi airway and parenchymal TRM, whereas most CD11alo airway TRM did not produce IFN-γ. In vivo production of IFN-γ was clearly detectable in CD11ahi airway and parenchymal TRM but essentially absent in CD11alo airway TRM, irrespective of airway-instilled peptide concentration or influenza reinfection. The majority of IFN-γ-producing airway TRM in vivo were CD11ahi, suggesting recent airway entry. These results question the contribution of long-term CD11alo airway TRM to influenza immunity and reinforce the importance of defining TRM tissue compartment-specific contributions to protective immunity.

Influenza-Induced CD103+ T Resident Memory Cells Exhibit Enhanced Functional Avidity over CD103- Memory T Cells in the Mediastinal Lymph Node.

Influenza virus-specific tissue-resident memory CD8 T cells (Trms) targeting conserved viral proteins provide strain-transcending heterosubtypic immunity to infection. Trms in the lung combat reinfection through rapid cytolytic function and production of inflammatory cytokines to recruit other immune cells. Influenza-specific Trms are also generated in the lung draining mediastinal lymph node (mLN) and can provide immunity to heterologous virus infection in this tissue, although their role in combating influenza infection is less well defined. Functional avidity, a measure of T cell sensitivity to Ag stimulation, correlates with control of viral infection and may be important for immune detection of recently infected cells, when low numbers of surface peptide-MHC complexes are displayed. However, the functional avidity of influenza-specific Trms has not been previously compared with that of other memory CD8 T cell subsets. In this article, a methodology is presented to compare the functional avidity of CD8 T cell subsets across murine tissues, with a focus on influenza-specific mLNs compared with splenic CD8 T cells, by stimulating both populations in the same well to account for CD8 T cell-extrinsic variables. The functional avidity of influenza-specific mLN effector CD8 T cells is slightly increased relative to splenic effector CD8 T cells. However, CD103+ mLN Trms display increased functional avidity compared with splenic memory CD8 T cells and CD103- memory CD8 T cells within the mLN. In contrast, lung-derived CD103+ Trms did not exhibit enhanced functional avidity. mLN CD103+ Trms also exhibit increased TCR expression, providing a potential mechanism for their enhanced functional avidity.

Bone strength and composition in spacefaring rodents: systematic review and meta-analysis.

Studying the effects of space travel on bone of experimental animals provides unique advantages, including the ability to perform post-mortem analysis and mechanical testing. To synthesize the available data to assess how much and how consistently bone strength and composition parameters are affected by spaceflight, we systematically identified studies reporting bone health in spacefaring animals from Medline, Embase, Web of Science, BIOSIS, and NASA Technical reports. Previously, we reported the effect of spaceflight on bone architecture and turnover in rodents and primates. For this study, we selected 28 articles reporting bone strength and composition in 60 rats and 60 mice from 17 space missions ranging from 7 to 33 days in duration. Whole bone mechanical indices were significantly decreased in spaceflight rodents, with the percent difference between spaceflight and ground control animals for maximum load of -15.24% [Confidence interval: -22.32, -8.17]. Bone mineral density and calcium content were significantly decreased in spaceflight rodents by -3.13% [-4.96, -1.29] and -1.75% [-2.97, -0.52] respectively. Thus, large deficits in bone architecture (6% loss in cortical area identified in a previous study) as well as changes in bone mass and tissue composition likely lead to bone strength reduction in spaceflight animals.

Bone health in spacefaring rodents and primates: systematic review and meta-analysis.

Animals in space exploration studies serve both as a model for human physiology and as a means to understand the physiological effects of microgravity. To quantify the microgravity-induced changes to bone health in animals, we systematically searched Medline, Embase, Web of Science, BIOSIS, and NASA Technical reports. We selected 40 papers focusing on the bone health of 95 rats, 61 mice, and 9 rhesus monkeys from 22 space missions. The percentage difference from ground control in rodents was -24.1% [Confidence interval: -43.4, -4.9] for trabecular bone volume fraction and -5.9% [-8.0, -3.8] for the cortical area. In primates, trabecular bone volume fraction was lower by -25.2% [-35.6, -14.7] in spaceflight animals compared to GC. Bone formation indices in rodent trabecular and cortical bone were significantly lower in microgravity. In contrast, osteoclast numbers were not affected in rats and were variably affected in mice. Thus, microgravity induces bone deficits in rodents and primates likely through the suppression of bone formation.

Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation.

Antimalarial antibody responses are essential for mediating the clearance of Plasmodium parasite-infected RBCs from infected hosts. However, the rapid appearance of large numbers of plasmablasts in Plasmodium-infected hosts can suppress the development and function of durable humoral immunity. Here, we identify that the formation of plasmablast populations in Plasmodium-infected mice is mechanistically linked to both hemolysis-induced exposure of phosphatidylserine on damaged RBCs and inflammatory cues. We also show that virus and Trypanosoma infections known to trigger hemolytic anemia and high-grade inflammation also induce exuberant plasmablast responses. The induction of hemolysis or administration of RBC membrane ghosts increases plasmablast differentiation. The phosphatidylserine receptor Axl is critical for optimal plasmablast formation, and blocking phosphatidylserine limits plasmablast expansions and reduces Plasmodium parasite burden in vivo. Our findings support that strategies aimed at modulating polyclonal B cell activation and phosphatidylserine exposure may improve immune responses against Plasmodium parasites and potentially other infectious diseases that are associated with anemia.