Role of regulatory T cells in long-term immune dysfunction associated with severe sepsis.
OBJECTIVE
To investigate the role of regulatory T cells in the modulation of long-term immune dysfunction during experimental sepsis. It is well established that sepsis predisposes to development of a pronounced immunosuppression. Nevertheless, the mechanisms underlying the immune dysfunction after sepsis are still not well understood.


METHODS
Prospective experimental study.


METHODS
University research laboratory.


METHODS
Wild-type mice underwent cecal ligation and puncture and were treated with antibiotic during 3 days after surgery. On days 1, 7, or 15 after cecal ligation and puncture, the frequency of regulatory T cells, proliferation of CD4 T cells and bacterial counts were evaluated. Fifteen days after cecal ligation and puncture, surviving mice underwent secondary pulmonary infection by intranasal inoculation of nonlethal dose of Legionella pneumophila. Some mice received agonistic glucocorticoid-induced tumor necrosis factor receptor antibody (DTA-1) before induction of secondary infection.


RESULTS
Mice surviving cecal ligation and puncture showed a markedly increased frequency of regulatory T cells in thymus and spleen, which was associated with reduced proliferation of CD4 T cells. Fifteen days after cecal ligation and puncture, all sepsis-surviving mice succumbed to nonlethal injection of L. pneumophila. Treatment of mice with DTA-1 antibody reduced frequency of regulatory T cells, restored CD4 T cell proliferation, reduced the levels of bacteria in spleen, and markedly improved survival of L. pneumophila infection.


CONCLUSIONS
These findings suggest that regulatory T cells play an important role in the progression and establishment of immune dysfunction observed in experimental sepsis.
Nascimento
Daniele C
DC
Departments of Biochemistry and Immunology, University of São Paulo, Ribeirao Preto, São Paulo, Brazil.
Alves-Filho
José C
JC
Sônego
Fabiane
F
Fukada
Sandra Y
SY
Pereira
Marcelo S
MS
Benjamim
Claudia
C
Zamboni
Dario S
DS
Silva
João S
JS
Cunha
Fernando Q
FQ
D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance; D016952:Legionella pneumophila; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018709:Statistics, Nonparametric; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D017252:CD3 Complex; D015704:CD4 Antigens; D001219:Aspartate Aminotransferases