Memory cytotoxic T lymphocytes (CTLs) are able to provide protections to the host against repeated insults from intracellular pathogens. However, it has not been completely understood how the effector functions of memory CTLs are induced upon antigen challenge, which is directly related to the efficacy of their protection. Third signal cytokines, such as IL-12 and type I interferon, have been suggested to be involved in the protective function of memory CTLs, but direct evidence is warranted. In this report, we found that memory CTLs need to be reactivated to exert effector functions. Infusion of a large population of quiescent memory CTLs did not lead to cancer control in tumor-bearing mice, whereas infusion of a reactivated memory CTL population did. This reactivation of memory CTLs requires cytokines such as IL-12 in addition to antigen but was less dependent upon costimulation and IL-2 compared to naive CTLs. Memory CTLs responded more quickly and with greater strength than their naive counterparts upon stimulation, which is associated with higher upregulation of important transcription factors such as T-bet and phosphorylated STAT4. In addition, memory CTLs underwent less expansion than naive CTLs upon pathogen challenge. In conclusion, effector functions of established memory CTLs may be affected by certain cytokines such as IL-12 and type I IFN. Thus, a pathogen's ability to induce cytokines could contribute to the efficacy of protection of an established memory CTL population.
INTRODUCTION: Mycobacterium avium complex organisms are ubiquitous organisms whose immune response often leads to progressive parenchymal lung disease and bronchiectasis, increasing the risk for secondary infections. Secondary infections with organisms such as M. abscessus, P. aeruginosa and S. aureus are well described, however dual infections with MAC and Nocardia species are very uncommon. Only two cases of MAC with pulmonary nocardiosis, both due to N. cyriacigeorgica, have ever been described. Here we described the first case of MAC coinfection with N. nova. CASE PRESENTATION:A 62-year-old female with a 40-pack-year smoking history and COPD, presented as an out-patient for annual lung cancer screening and complaints of dyspnea with hemoptysis for one year. CT revealed progressive multifocal ground glass attenuation, infiltrative changes, and diffuse reticular and nodular parenchymal changes bilaterally. Given her markedly abnormal lungs, sputum studies were collected and grew MAC. Over one month, her symptoms worsened and she eventually required supplemental oxygen. A second sputum study was collected, revealing N. nova in addition to the previously seen MAC. The patient was admitted to the hospital and treated with imipenem plus high-dose trimethoprim-sulfamethoxazole to treat nocardiosis. She rapidly improved over the course of four days and was discharged on ceftriaxone plus oral TMP-SMX. After four weeks, azithromycin, rifampin, and ethambutol were added to cover MAC. The patient has not experienced any subsequent hospitalizations.DISCUSSION: Our patient's worsening dyspnea and persistent cough with hemoptysis for one year likely represented her chronic, indolent MAC infection. Subsequently, we suspect her subacute decompensation over one month to be the result of the superimposed Nocardia infection given the aggressive nature of Nocardia infections and the rapid improvement over four days on imipenem and TMP-SMX, a regimen focused solely on Nocardia. COPD has long been recognized as a risk factor for MAC, and more recently has been identified as a secondary risk factor for Nocardia infection. Although most cases of nocardiosis have been described in individuals with cell-mediated immune defects, a recent study identifies COPD to be a contributing risk factor in 31% of nocardiosis. Additionally, MAC has been shown to cause additional parenchymal lung disease and bronchiecstatsis, both of which may serve as risk factors for pulmonary nocardiosis due to alteration of ciliary motility and epithelial damage.CONCLUSIONS: This case brings attention to the first documented case of MAC coinfection with N. nova. Although further research needs to be completed before associations and causation between chronic lung disease, MAC, and Nocardia may be discerned, this case emphasizes the importance of clinicians to evaluate for secondary pathogens in the setting of clinically worsening MAC lung disease.
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