Two Host Factors Regulate Persistence of H7a-Specific T Cells Injected in Tumor-Bearing Mice

Background

Injection of CD8 T cells primed against immunodominant minor histocompatibility antigens (MiHA) such as H7^a can eradicate leukemia and solid tumors. To understand why MiHA-targeted T cells have such a potent antitumor effect it is essential to evaluate their in vivo behavior. In the present work, we therefore addressed two specific questions: what is the proliferative dynamics of H7^a-specifc T cells in tumors, and do H7^a-specific T cells persist long-term after adoptive transfer?

Methodology/Principal Findings

By day 3 after adoptive transfer, we observed a selective infiltration of melanomas by anti-H7^a T cells. Over the next five days, anti-H7^a T cells expanded massively in the tumor but not in the spleen. Thus, by day 8 after injection, anti-H7^a T cells in the tumor had undergone more cell divisions than those in the spleen. These data strongly suggest that anti-H7^a T cells proliferate preferentially and extensively in the tumors. We also found that two host factors regulated long-term persistence of anti-H7^a memory T cells: thymic function and expression of H7^a by host cells. On day 100, anti-H7^a memory T cells were abundant in euthymic H7^a-negative (B10.H7^b) mice, present in low numbers in thymectomized H7^a-positive (B10) hosts, and undetectable in euthymic H7^a-positive recipients.

Conclusions/Significance

Although in general the tumor environment is not propitious to T-cell invasion and expansion, the present work shows that this limitation may be overcome by adoptive transfer of primed CD8 T cells targeted to an immunodominant MiHA (here H7^a). At least in some cases, prolonged persistence of adoptively transferred T cells may be valuable for prevention of late cancer relapse in adoptive hosts. Our findings therefore suggest that it may be advantageous to target MiHAs with a restricted tissue distribution in order to promote persistence of memory T cells and thereby minimize the risk of cancer recurrence.     

Non Mycobacterial Virulence Genes in the Genome of the Emerging Pathogen Mycobacterium abscessus

Mycobacterium abscessus is an emerging rapidly growing mycobacterium (RGM) causing a pseudotuberculous lung disease to which patients with cystic fibrosis (CF) are particularly susceptible. We report here its complete genome sequence. The genome of M. abscessus (CIP 104536T) consists of a 5,067,172-bp circular chromosome including 4920 predicted coding sequences (CDS), an 81-kb full-length prophage and 5 IS elements, and a 23-kb mercury resistance plasmid almost identical to pMM23 from Mycobacterium marinum. The chromosome encodes many virulence proteins and virulence protein families absent or present in only small numbers in the model RGM species Mycobacterium smegmatis. Many of these proteins are encoded by genes belonging to a “mycobacterial” gene pool (e.g. PE and PPE proteins, MCE and YrbE proteins, lipoprotein LpqH precursors). However, many others (e.g. phospholipase C, MgtC, MsrA, ABC Fe(3+) transporter) appear to have been horizontally acquired from distantly related environmental bacteria with a high G+C content, mostly actinobacteria (e.g. Rhodococcus sp., Streptomyces sp.) and pseudomonads. We also identified several metabolic regions acquired from actinobacteria and pseudomonads (relating to phenazine biosynthesis, homogentisate catabolism, phenylacetic acid degradation, DNA degradation) not present in the M. smegmatis genome. Many of the “non mycobacterial” factors detected in M. abscessus are also present in two of the pathogens most frequently isolated from CF patients, Pseudomonas aeruginosa and Burkholderia cepacia. This study elucidates the genetic basis of the unique pathogenicity of M. abscessus among RGM, and raises the question of similar mechanisms of pathogenicity shared by unrelated organisms in CF patients.     

Hindlimb unloading depresses corneal epithelial wound healing in mice.

C57BL/6 mice were subjected to hindlimb unloading (HU) for a period of 3 wk to determine the possible effects on epithelial wound healing. A standardized corneal epithelial wound was performed, and parameters of the inflammatory response and reepithelialization were analyzed over an observation period of 96 h. Wound closure was significantly retarded in mice during HU with reepithelialization being delayed by approximately 12 h. Both epithelial migration and cell division were significantly depressed and delayed. The inflammatory response to epithelial wounding was also significantly altered during HU. Neutrophils, as detected by the Gr-1 marker, were initially elevated above normal levels before wounding and during the first few hours afterward, but there was a significant reduction in neutrophil response to wounding at times where neutrophil influx and migration in controls were vigorous. A similar pattern was seen with CD11b+CD11c+ cells (monocyte lineage). Langerhans cells are normally resident within the peripheral corneal epithelium. They respond to injury by initially leaving the epithelial site within 6 h and returning to normal levels by 96 h, 2 days after reepithelialization is complete. During HU, this pattern is distinctly different, with Langerhans cell numbers slowly diminishing, reaching a nadir at 96 h, which is significantly below normal. Evidence for systemic effects of HU is provided by findings that collagen deposition within subcutaneous sponges was significantly reduced during HU. In conclusion, HU, a ground-based model simulating some physiological aspects of spaceflight, impairs wound repair of corneas. Multiple factors, both local and systemic, likely contribute to this delayed wound healing.     

Exercise intensity prescription in obese individuals

The main purpose of this study was to evaluate the relationship between different methods proposed by the American College of Sports Medicine (ACSM) to prescribe exercise intensity using heart rate (HR) and oxygen uptake (VO2) in obese individuals. Sixty-eight overweight to severely obese adults were divided into three groups (tertile) based on their BMI. The groups were T1 group (BMI = 30.5 +/- 1.5, n = 23), T2 group (BMI = 34.3 +/- 1.0, n = 23), and T3 group (BMI = 40.2 +/- 3.7, n = 22). All subjects performed a graded exercise test using a ramp protocol on a treadmill. Individual linear regressions between %HR reserve (%HRR) and %VO2 reserve (%VO2R), %HRR and %VO2 peak (%VO2peak), %maximal HR (%HRmax) and %VO2R, and %HRmax and %VO2peak were calculated. When all the subjects were grouped together, the %HRR-%VO2R mean regression was partially related to the line of identity, while the %HRR-%VO2peak, %HRmax-%VO2R, and %HRmax-%VO2peak mean regressions were all significantly different than the line of identity (P < 0.001). The degree of obesity accounted for approximately 15% of the variation for both %HRR-%VO2R and %HRR-%VO2peak mean regressions. The %HRmax-%VO2R and %HRmax-%VO2peak mean regressions were not affected by the degree of obesity but resting HR accounted for 28-37% of the variation. The relationship between the exercise intensity determined by the %HRR-%VO2R and the %HRR-%VO2peak mean regression seems to be influenced by the degree of obesity. The degree of obesity does not affect the relationship between exercise intensity generated by the %HRmax-%VO2R or %HRmax-%VO2peak equations but the resting HR does.     

Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence

Tuberculosis (TB) is characterized by a tight interplay between Mycobacterium tuberculosis and host cells within granulomas. These cellular aggregates restrict bacterial spreading, but do not kill all the bacilli, which can persist for years. In-depth investigation of M. tuberculosis interactions with granuloma-specific cell populations are needed to gain insight into mycobacterial persistence, and to better understand the physiopathology of the disease. We have analyzed the formation of foamy macrophages (FMs), a granuloma-specific cell population characterized by its high lipid content, and studied their interaction with the tubercle bacillus. Within our in vitro human granuloma model, M. tuberculosis long chain fatty acids, namely oxygenated mycolic acids (MA), triggered the differentiation of human monocyte-derived macrophages into FMs. In these cells, mycobacteria no longer replicated and switched to a dormant non-replicative state. Electron microscopy observation of M. tuberculosis–infected FMs showed that the mycobacteria-containing phagosomes migrate towards host cell lipid bodies (LB), a process which culminates with the engulfment of the bacillus into the lipid droplets and with the accumulation of lipids within the microbe. Altogether, our results suggest that oxygenated mycolic acids from M. tuberculosis play a crucial role in the differentiation of macrophages into FMs. These cells might constitute a reservoir used by the tubercle bacillus for long-term persistence within its human host, and could provide a relevant model for the screening of new antimicrobials against non-replicating persistent mycobacteria.