Interleukin 10 enhanced CD8+ T cell activity and reduced CD8+ T cell apoptosis in patients with diffuse large B cell lymphoma.

The pleiotropic cytokine interleukin (IL)-10 is best characterized by its ability to downregulate inflammation and promote peripheral tolerance. On the other hand, IL-10 was also found to maintain the effector response of CD8+ T cells and promote the expansion of tumor-resident CD8+ T cells. In diffuse large B cell lymphoma (DLBCL), the role of IL-10 has been characterized in tumor cells but not in CD8+ T cells. We found that CD8+ T cells in DLBCL presented robust interferon (IFN)-γ expression early during TCR-activation but could not maintain this response later on, which was characterized by significantly lower CD8+ T cell degranulation and higher apoptosis. These observations were associated with higher PD-1 expression in DLBCL CD8+ T cells. Furthermore, the PD-1+ cells were strongly enriched in the IFN-γ+, but not the IFN-γ-, fraction. Interestingly, exogenous IL-10 significantly improved the survival of DLBCL CD8+ T cells, and resulted in significantly higher IFN-γ, ganzyme A and granzyme B expression in the absence of CD19+ tumor cells, and significantly improved CD8+ T cell-mediated specific lysis of CD19+ tumor cells. IL-10 did not alter the expression of PD-1 in DLBCL CD8+ T cells, but curiously, IL-10-treated DLBCL CD8+ T cells were less susceptible to PD-L1-mediated apoptosis. We then demonstrated that IL-10 treatment significantly elevated the expression of pro-survival factor Bcl-2. Blocking IL-10 resulted in higher apoptosis, fewer IFN-γ+ CD8+ T cells, and lower Bcl-2 expression. IL-10 also significantly increased STAT3, but not STAT1, phosphorylation in CD8+ T cells. Together, these results suggested that IL-10 could enhance CD8+ T cell inflammation in DLBCL patients.

CD19(+) CD20(-) CD27(hi) IL-s10-producing B cells are overrepresented in R-CHOP-treated DLBCL patients in complete remission.

Treatment of diffuse large B cell lymphoma (DLBCL) with rituximab, an anti-CD20 monoclonal antibody, has resulted in significantly improved patient responses with longer event-free intervals and higher overall survival rates. However, since rituximab depletes all CD20-expressing cells, including noncancerous B cells, the effects of rituximab on the normal immunity of DLBCL patients under remission need to be examined. Here, we observed that DLBCL patients under remission contained significantly lower frequencies of total B cells, with a significantly overrepresented interleukin (IL)-10-producing B cell (B10) population in the peripheral blood. Further examination confirmed that a large fraction of B10 cells was CD20(-) CD27(hi) plasmablasts, possibly explaining the persistence of B10 cells after R-CHOP treatment. We also observed that the percentage of B10 cells in DLBCL patients in remission gradually reduced during the first year of achieving complete remission, primarily due to the replenishment of non-B10 B cells. Despite this, the percentage of B10 cells in DLBCL patients after 1 year of achieving complete remission was still higher than that in controls. CD4(+) and CD8(+) T cells cocultured with B10-enriched B cells secreted significantly lower levels of proinflammatory cytokines IFN-g and TNF-a, compared to those incubated with B10-depleted B cells. Together, our data observed a long-lasting overrepresentation of B10 cells in DLBCL patients under remission. Whether this change could impact on the overall anti-tumor immunity during remission requires further studies.

Creating the vaccination improvement potential index.

Background: Numerous social and behavioral factors have been implicated in vaccination coverage. There is no single measure that describes a country's ability to improve or maintain its immunization coverage. Methods: We estimated the "Vaccination Improvement Potential" (VIP) by taking the geometric mean of 13 different indicators on health financing, vaccine confidence, and socio-demographics for more than 200 countries across 30 years. Potential VIP Index values range from 0 to 1, with a higher score indicating greater potential to improve or maintain high vaccination rates. Findings: In 1990, the mean VIP score was 0.49 (range = 0.13 to 0.86). In 2019, the mean score was 0.59 (range = 0.25 to 0.84). Consistent high performers included countries in Western Europe and high-income North America and East Asia. Important differences in subcomponents of the index drove major trends including vaccine hesitancy in Western Europe and Asia as well as lower levels of per capita health spending and development assistance in sub-Saharan Africa. Interpretation: The VIP Index is a first-of-its-kind tool for understanding the capacity that exists in a country to realize improved immunization rates. It is a new resource that can guide researchers, policymakers, and health officials to more effectively deploy resources to realize improvements in vaccination coverage, assess the impact of those improvements, and identify countries that might require additional support to improve vaccine coverage. Funding: Merck Sharp & Dohme Corp.

Dynamics of infection-elicited SARS-CoV-2 antibodies in children over time.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits an antibody response that targets several viral proteins including spike (S) and nucleocapsid (N); S is the major target of neutralizing antibodies. Here, we assess levels of anti-N binding antibodies and anti-S neutralizing antibodies in unvaccinated children compared with unvaccinated older adults following infection. Specifically, we examine neutralization and anti-N binding by sera collected up to 52 weeks following SARS-CoV-2 infection in children and compare these to a cohort of adults, including older adults, most of whom had mild infections that did not require hospitalization. Neutralizing antibody titers were lower in children than adults early after infection, but by 6 months titers were similar between age groups. The neutralizing activity of the children's sera decreased modestly from one to six months; a pattern that was not significantly different from that observed in adults. However, infection of children induced much lower levels of anti-N antibodies than in adults, and levels of these anti-N antibodies decreased more rapidly in children than in adults, including older adults. These results highlight age-related differences in the antibody responses to SARS-CoV-2 proteins and, as vaccines for children are introduced, may provide comparator data for the longevity of infection-elicited and vaccination-induced neutralizing antibody responses.

A Negative Feedback Loop Between Autophagy and Immune Responses in Mycobacterium leprae Infection.

The obligate intracellular bacterium Mycobacterium leprae is the causative agent of leprosy and primarily infects macrophages, leading to irreversible nerve damage and deformities. So far, the underlying reasons allowing M. leprae to persist and propagate in macrophages, despite the presence of cellular immunity, are still a mystery. Here, we investigated the role of autophagy, a cellular process that degrades cytosolic materials and intracellular pathogens, in M. leprae infection. We found that live M. leprae infection of macrophages resulted in significantly elevated autophagy level. However, macrophages with high autophagy levels preferentially expressed lower levels of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6, IL-12, and tumor necrosis factor-α, and preferentially primed anti-inflammatory T cells responses, characterized by high IL-10 and low interferon-γ, granzyme B, and perforin responses. These anti-inflammatory T cells could suppress further induction of autophagy, leading to improved survival of intracellular M. leprae in infected macrophages. Therefore, these data demonstrated that although autophagy had a role in eliminating intracellular pathogens, the induction of autophagy resulted in anti-inflammatory immune responses, which suppressed autophagy in a negative feedback loop and allowed the persistence of M. leprae.