Neonatal T Cells in an Adult Lung Environment Are Competent to Resolve Pneumocystis carinii Pneumonia

Abstract

Initiation of the pulmonary inflammatory response to Pneumocystis carinii is delayed by 3 wk in mice infected as neonates compared with adults. There was no difference in the proliferative response of draining lymph node T cells from mice infected as neonates compared with adults when stimulated in vitro with either Con A or anti-CD3 mAb. However, TNF-α and IFN-γ mRNA expression in the lungs of P. carinii-infected neonates was significantly lower than in adults indicating a lack of appropriate activation signaling in the local environment. This may have been due to active suppression because TGF-β mRNA expression was significantly elevated in neonatal lungs compared with adults. To determine whether T cells from 10-day-old mice would effect resolution of P. carinii if harbored in an adult lung environment, cells were adoptively transferred to SCID mice with established P. carinii infections. There was no difference in the kinetics of T cell migration into the lungs or of clearance of P. carinii organisms when SCID mice were reconstituted with splenocytes from young mice as compared with adult mice. Furthermore, splenocytes from young mice stimulated both TNF-α and IFN-γ mRNA expression to levels that were similar to that in the lungs of SCID mice reconstituted with adult cells. These data indicate that neonatal lymphocytes are competent to resolve P. carinii infection when harbored in an adult lung environment, suggesting that the neonatal lung environment, and not the T cells, is ineffective at responding to P. carinii infection.

Passive Immunization of Neonatal Mice againstPneumocystis cariniif. sp.murisEnhances Control of Infection without Stimulating Inflammation

“…It was previously reported that the delayed clearance of Pneumocystis infection seen in mice infected as neonates corresponds to delayed upregulation of proinflammatory cytokines and chemokines (9,33). Surprisingly, there was no difference in the concentrations of TNF-␣, IFN␥, MCP-1, and IL-6 in the BALF of Pneumocystis-infected pups from immunized dams compared to those of pups born to naïve dams through day 19 postinfection (Fig.…”

“…It has previously been published that there is a 3-week delay in the host response of mice infected with Pneumocystis as neonates compared to the response of mice infected as adults (8,9,33). To determine whether alveolar macrophage activation is also delayed in neonatal mice in response to Pneumocystis, we used flow cytometry to examine macrophage markers at various times postinfection.…”

“…Passive antibody has been shown to decrease airway inflammation in a murine model of respiratory syncytial virus infection (28) and prolong survival of mice infected with Cryptococcus neoformans by changing the characteristics and intensity of the pulmonary cellular and cytokine response (7). One explanation for the lack of generation of an inflammatory response to Pneumocystis in neonatal mice might be that there is likely transforming growth factor ␤ present in the postnatally developing lungs (33), which has been shown to inhibit Fc␥ receptor signaling in murine macrophages (35). However, a direct connection in this regard has not been proven.…”

“…muris (the mouse-specific species) have a delayed pulmonary immune response compared to adult mice (8,9). This delay in the immune response to Pneumocystis was characterized by depressed lung proinflammatory cytokines and chemokines, T-cell migration, and antibody production in neonates over the first 3 weeks of life (8,9,33).…”

Scavenger Receptor A Dampens Induction of Inflammation in Response to the Fungal PathogenPneumocystis carinii

“…We have extensive data demonstrating that there is a significant delay in the ability of neonatal mice to clear P. carinii compared to adult mice, and this delay corresponds to delayed activation of alveolar macrophages, delayed entry of CD4 ϩ cells into the lungs, and delayed specific antibody responses to P. carinii (10,15,40). Consistent with our observations in adults, neonatally infected SRAKO mice had elevated numbers of CD4 ϩ cells in the lungs and draining lymph nodes compared to wild-type pups.…”