Acute inflammation alters lung lymphocytes and potentiates innate-like behavior in young mouse lung CD8 T cells, resembling lung CD8 T cells from old mice.

Inflammation plays a significant role in lung infection including that caused by Mycobacterium tuberculosis, in which both adaptive and innate lymphocytes can affect infection control. How inflammation affects infection is understood in a broad sense, including inflammaging (chronic inflammation) seen in the elderly, but the explicit role that inflammation can play in regulation of lymphocyte function is not known. To fill this knowledge gap, we used an acute lipopolysaccharide (LPS) treatment in young mice and studied lymphocyte responses, focusing on CD8 T cell subsets. LPS treatment decreased the total numbers of T cells in the lungs of LPS mice while also increasing the number of activated T cells. We demonstrate that lung CD8 T cells from LPS mice became capable of an antigen independent innate-like IFN-γ secretion, dependent on IL-12p70 stimulation, paralleling innate-like IFN-γ secretion of lung CD8 T cells from old mice. Overall, this study provides information on how acute inflammation can affect lymphocytes, particularly CD8 T cells, which could potentially affect immune control of various disease states.

Recall responses in the lung environment are impacted by age in a pilot study of Mycobacterium bovis-BCG vaccinated rhesus macaques.

Age-related changes in the immune system increase susceptibility to infectious diseases. Vaccines are an important tool to prevent infection or boost immunological memory; however, vaccines are less effective in aged individuals. In order to protect our aging population from the threat of infectious diseases, we must gain a better understanding of age-related alterations in the immune response at the site of infection. The lung is one site of frequent infection in older individuals. In this study, we expanded on our previous work to study vaccine-induced immune responses in the local lung environment in a pilot study of aged rhesus macaques. To do this, we developed an in vivo model to probe recall responses to tuberculin challenge in the lungs 8 weeks and 16 weeks post-Mycobacterium bovis BCG vaccination by performing targeted bronchoalveolar lavages. In parallel, we determined peripheral blood responses in vaccinated animals to compare systemic and local tissue responses to tuberculin challenge. We found that following lung tuberculin challenge 8 weeks post-vaccination, aged animals had reduced T cell responses, particularly within the CD8+ T cell compartment. Aged animals had decreased CD8+ effector and memory T cell recall responses and less activated CD8+ T cells. This diminished lung CD8+ T cell response in aged animals was maintained over time. Despite changes in the CD8+ T cell compartment, lung CD4+ T cell responses were similar between age groups. In the peripheral blood, we observed age-related changes in immune cell populations and plasma levels of immune mediators that were present prior to vaccination. Lastly, we found that peripheral blood mononuclear cells from aged BCG-vaccinated animals were functional in their response to antigen stimulation, behaving in a similar manner to those from their adult counterparts. These systemic observations were similar to those found in our previous study of BCG-vaccinated baboons, supporting the notion that tissue immune responses, and not systemic responses, to vaccination and challenge are impaired with age. These findings expand on our previous work to show that in addition to the skin, age-related changes in the lung environment impact recall immune responses to vaccination and challenge. The impact of age on local tissue responses to infectious challenge should be accounted for in the development of therapeutics or medical interventions aimed at boosting immune recall responses of aged individuals.

IL-10 Receptor Blockade Delivered Simultaneously with Bacillus Calmette-Guérin Vaccination Sustains Long-Term Protection against Mycobacterium tuberculosis Infection in Mice.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) immunization still remains the best vaccination strategy available to control the development of active tuberculosis. Protection afforded by BCG vaccination gradually wanes over time and although booster strategies have promise, they remain under development. An alternative approach is to improve BCG efficacy through host-directed therapy. Building upon prior knowledge that blockade of IL-10R1 during early Mycobacterium tuberculosis infection improves and extends control of M. tuberculosis infection in mice, we employed a combined anti-IL-10R1/BCG vaccine strategy. An s.c. single vaccination of BCG/anti-IL10-R1 increased the numbers of CD4+ and CD8+ central memory T cells and reduced Th1 and Th17 cytokine levels in the lung for up to 7 wk postvaccination. Subsequent M. tuberculosis challenge in mice showed both an early (4 wk) and sustained long-term (47 wk) control of infection, which was associated with increased survival. In contrast, protection of BCG/saline-vaccinated mice waned 8 wk after M. tuberculosis infection. Our findings demonstrate that a single and simultaneous vaccination with BCG/anti-IL10-R1 sustains long-term protection, identifying a promising approach to enhance and extend the current BCG-mediated protection against TB.

Acute Inflammation Confers Enhanced Protection against Mycobacterium tuberculosis Infection in Mice.

Inflammation plays a crucial role in the control of Mycobacterium tuberculosis infection. In this study, we demonstrate that an inflammatory pulmonary environment at the time of infection mediated by lipopolysaccharide treatment in mice confers enhanced protection against M. tuberculosis for up to 6 months postinfection. This early and transient inflammatory environment was associated with a neutrophil and CD11b+ cell influx and increased inflammatory cytokines. In vitro infection demonstrated that neutrophils from lipopolysaccharide-treated mice exhibited increased association with M. tuberculosis and had a greater innate capacity for killing M. tuberculosis. Finally, partial depletion of neutrophils in lipopolysaccharide-treated mice showed an increase in M. tuberculosis burden, suggesting neutrophils played a part in the protection observed in lipopolysaccharide-treated mice. These results indicate a positive role for an inflammatory environment in the initial stages of M. tuberculosis infection and suggest that acute inflammation at the time of M. tuberculosis infection can positively alter disease outcome. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis disease, is estimated to infect one-fourth of the world's population and is one of the leading causes of death due to an infectious disease worldwide. The high-level variability in tuberculosis disease responses in the human populace may be linked to immune processes related to inflammation. In many cases, inflammation appears to exasperate tuberculosis responses; however, some evidence suggests inflammatory processes improve control of M. tuberculosis infection. Here, we show an acute inflammatory stimulus in mice provides protection against M. tuberculosis for up to 6 months, suggesting acute inflammation can positively affect M. tuberculosis infection outcome.

Local immune responses to tuberculin skin challenge in Mycobacterium bovis BCG-vaccinated baboons: a pilot study of younger and older animals.

Individuals over the age of 65 are highly susceptible to infectious diseases, which account for one-third of deaths in this age group. Vaccines are a primary tool to combat infection, yet they are less effective in the elderly population. While many groups have aimed to address this problem by studying vaccine-induced peripheral blood responses in the elderly, work from our lab and others demonstrate that immune responses to vaccination and infectious challenge may differ between tissue sites and the periphery. In this pilot study, we established an in vivo delayed-type hypersensitivity model of Mycobacterium bovis BCG vaccination and tuberculin skin test in two adult and two aged baboons. Vaccination generates BCG-specific immune cells that are recruited to the skin upon tuberculin challenge. We tested short term recall responses (8 weeks post-vaccination) and long term recall responses (25 weeks post-vaccination) by performing skin punch biopsies around the site of tuberculin injection. In short term recall responses, we found increased oxidation and decreased production of immune proteins in aged baboon skin at the site of TST challenge, in comparison to adult skin. Differences between adult and aged animals normalized in the long term response to tuberculin. In vitro, aged peripheral blood mononuclear cells had increased migration and functional responses to antigen-specific stimulation, suggesting that age-related changes in the tissue in vivo impairs aged immune recall responses to antigenic challenge. These findings highlight the impact of age-associated changes in the local tissue environment in memory recall responses, which may be more broadly applied to the study of other tissues. Moreover, these findings should be considered in future studies aimed at understanding and improving aging immune responses to vaccination and tissue challenge.

Tuberculosis in the elderly: Why inflammation matters.

Growing old is associated with an increase in the basal inflammatory state of an individual and susceptibility to many diseases, including infectious diseases. Evidence is growing to support the concept that inflammation and disease susceptibility in the elderly is linked. Our studies focus on the infectious disease tuberculosis (TB), which is caused by Mycobacterium tuberculosis (M.tb), a pathogen that infects approximately one fourth of the world's population. Aging is a major risk factor for developing TB, and inflammation has been strongly implicated. In this review we will discuss the relationship between inflammation in the lung and susceptibility to develop and succumb to TB in old age. Further understanding of the relationship between inflammation, age, and M.tb will lead to informed decisions about TB prevention and treatment strategies that are uniquely designed for the elderly.