Elevated Levels of Interferon-γ Production by Memory T Cells Do Not Promote Transplant Tolerance Resistance in Aged Recipients

Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age) aged male recipients (greater than 12 months of age) transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ) in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Young and aged animals exhibit similar levels of IL-10 production.

<p>Spleen was examined for B220, CD4, CD8, and IL-10. Y-axis indicates percentage of B220+, CD4+, or CD8+ cells that were IL-10+. At least two to three animals were examined independently per group. </p

Memory T, not naive T, exhibit elevated production of IFN-γ, in young and old animals.

<p>(<b>A</b>) CD4 and CD8 memory T cells expand in aged animals. Young and aged animals, with and without skin graft, were examined for memory T cells 14 days post-transplant. At least two to three animals were examined independently per group. (<b>B</b>) Splenocytes were examined for CD4, CD8, CD44, and IFN-γ expression. Tnaive cells were gated as CD4+ CD44low or CD8+ CD44low, while Tmem were gated as CD44hi. The percentage of IFN-γ+ cells is plotted on the y-axis. At least two to three animals were examined independently per group. </p

A higher percentage of both CD4 and CD8 T cells from aged animals produce IFN-γ relative to those from young animals.

<p>Spleen and lymph node (LNC) from naive animals, grafted animals, and grafted, anti-CD45RB / anti-CD154-treated animals were examined 14 days after transplant, p<0.05*. Representative FACS plots are shown, <i>bottom</i>. 2 to 3 animals were examined independently in each group. </p

Neutralizing anti-interferon-γ antibody does not prolong graft survival in aged recipients.

<p>C57BL/6 mice received C3H skin grafts and were treated with anti-CD40L/anti-CD45RB antibodies with or without anti-interferon-γ antibodies (low dose at 200 ug or high dose at 600 ug). All antibodies were injected every other day for one week starting on the day of transplant. </p

Castration does not significantly modulate levels of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells.

<p>The effect of castration was examined on CD4+ and CD8+ T cells from spleen and lymph node of ungrafted and grafted, antibody-treated animals. Intracellular IFN-γ was examined two weeks after skin graft. Castration was performed 30 days before skin graft. In the absence of a skin graft, castration reduced the % of IFN-γ+ T cells in the lymph node, however, overall, castration did not significantly affect the percentages of IFN-γ production. </p

In contrast to young recipients, aged recipients are resistant to transplant tolerance induction.

<p>Young C57BL/6 recipients (less than 3-months of age) and aged C57BL/6 recipients (over 12-months of age) reject C3H/HeJ skin graft at same tempo. When treated with anti-CD45RB and anti-CD154 antibodies, 50% of skin grafts survive over 80 days. In contrast, antibody-treated aged recipients reject quickly (aged MST = 16.5 days versus young MST = 87.5 days, p>0.001**).</p