Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation

Abstract

The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55∆NS mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55∆NS mice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection.

TNFRp75‐dependent immune regulation of alveolar macrophages and neutrophils during early Mycobacterium tuberculosis and Mycobacterium bovis BCG infection

“…To study the effect of TNFRp75 in regulating macrophage functions, our initial experimental approach incorporated a bone marrow‐derived macrophages (BMDM) culture system, which we and others have used extensively to study macrophage responses to M . tuberculosis 34,35 . We first confirmed constitutive expression of TNFRp75 in unstimulated WT BMDM (Figure 1A).…”

“…Release of soluble TNFRp55 has been described to regulate macrophage activation and apoptosis during mycobacterial infection 34,36 . We have previously found that TNFRp75 deficiency is associated with the release of less TNFRp55 from DCs during M .…”

“…Macrophages are considered the primary target cells of M . tuberculosis , which express and release both soluble TNFRp55 and TNFRp75 that regulate TNF‐mediated activities including macrophage activation and survival in an autocrine fashion 8,16,34 . To study the effect of TNFRp75 in regulating macrophage functions, our initial experimental approach incorporated a bone marrow‐derived macrophages (BMDM) culture system, which we and others have used extensively to study macrophage responses to M .…”

“…In our earlier studies, we have also measured the levels of bioactive TNF in the BALF and shown that TNFRp75 shedding reduces bioavailability of TNF in M . tuberculosis ‐infected mice, 34 whereas deficiency of TNFRp75 increases bioavailability of TNF 30 . Therefore, we postulated that increased AM apoptosis to be a plausible mechanism to contribute to enhanced pulmonary immune protection in TNFRp75 −/− mice.…”

Mycobacterium Tuberculosis and Interactions with the Host Immune System: Opportunities for Nanoparticle Based Immunotherapeutics and Vaccines

“…Although a complex regulatory process, TNF-α is known to be an important factor that facilitates DC maturation towards specific T cell priming (59,60). Interestingly, while persistent TNFRp55 expression leads to potential defective T cell responses during chronic M. tuberculosis infection (61), sustained TNF-α expression by DCs enhances maturation and generates a much more robust T cell response (62). Thus, DCs are positioned to serve as an important link between innate and adaptive immunity and may act as useful targets for immunotherapy and vaccine development (63,64).…”