Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection.
Pneumocystis carinii pneumonia (PCP) is a frequent and serious opportunistic infection in immunocompromized patients. Although the pathogenesis of PCP-mediated lung injury is poorly understood, a central involvement of host inflammatory responses has been implicated. We have found that while the loss of specific T cell costimulatory signals increases susceptibility to the spontaneous pneumocystis infection, PCP-induced pulmonary injury (and subsequent morbidity and mortality) involves other intact costimulatory pathways. Mice that are genetically deficient for the costimulatory receptor CD154 (CD154 knockout (ko) mice) spontaneously developed PCP, consistent with the increased susceptibility of X-linked hyper IgM syndrome patients (caused by CD154 gene mutations) to P. carinii infection. In these mice PCP was manifested by progressive weight loss, dyspnea and death. In contrast, CD154 ko mice also genetically lacking ICAM1 (CD154 koxICAM1 ko) or CD28 (CD154 koxCD28 ko) costimulatory receptors had later onset of weight loss and significantly prolonged survival. Although onset of infection and age-matched P. carinii organism burden were equivalent, the CD154 single knockout mice had evidence of greater pulmonary inflammation vs. the double ko's. These findings suggest that costimulation-dependent T cell-mediated inflammation plays an important role in both susceptibility to and pathogenesis of PCP, and may identify potential molecular targets for novel immunomodulatory treatment approaches.
Baumgartner
Roxanne
R
Naval Medical Research Center, Bethesda, MD 20889, USA.
Durant
Pamela J
PJ
van Gessel
Yvonne
Y
Chattopadhyay
Suchismita
S
Beswick
Richard L
RL
Tadaki
Douglas K
DK
Lasbury
Mark E
ME
Lee
Chao-Hung
CH
Perrin
Peter J
PJ
Lee
Kelvin P
KP
D000818:Animals; D001835:Body Weight; D018106:CD28 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D011010:Pneumocystis / Q000472:pathogenicity*; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand