title: STAT4-dependent and -independent Th2 responses correlate with protective immunity against lung infection with Pneumocystis murina.
abstract: Although it is clear that the loss of CD4(+) T cells is a predisposing factor for the development of Pneumocystis pneumonia, specific Th mechanisms mediating protection are not well understood. Th1, Th2, and Th17 responses have each been implicated in protective responses during infection. As STAT4 may promote Th1 and Th17 development, yet antagonize Th2 development, we investigated its role in Pneumocystis murina host defense. STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and BALB/c mice 14 d postchallenge, but only BALB/c Stat4(-/-) mice demonstrated susceptibility to P. murina lung infection. BL/6 Stat4(-/-), but not BALB/c Stat4(-/-), mice maintained an enhanced alternatively activated (M2) macrophage signature in the lungs, which we have previously reported to be associated with enhanced P. murina clearance. In addition, anti-P. murina class-switched Abs were increased in BL/6 Stat4(-/-) mice, but not BALB/c Stat4(-/-) mice. Supporting our experimental observations, plasma from HIV-infected individuals colonized with Pneumocystis jirovecii contained significantly lower levels of the Th2 cytokines IL-4, IL-5, and IL-13 compared with HIV-infected individuals who were not colonized. Collectively, our data suggest that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Riley C
authors: RC
authors: Myers
authors: Chad W
authors: CW
authors: Dunaway
authors: Michael P
authors: MP
authors: Nelson
authors: Jennifer L
authors: JL
authors: Trevor
authors: Alison
authors: A
authors: Morris
authors: Chad
authors: C
authors: Steele
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000150:complications* / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011020:Pneumonia, Pneumocystis / Q000150:complications / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D050797:STAT4 Transcription Factor
references: J Immunol. 2011 Feb 15;186(4):2372-81
references: 21220696
references: Acta Haematol. 2012;127(2):110-4
references: 22178955
references: Clin Infect Dis. 2013 Jan;56(2):171-9
references: 23074306
references: Immunity. 2000 Nov;13(5):715-25
references: 11114383
references: J Infect. 2001 Feb;42(2):134-9
references: 11531320
references: J Clin Invest. 2005 Dec;115(12):3536-44
references: 16308571
references: J Pediatr. 1997 Jul;131(1 Pt 1):47-54
references: 9255191
references: J Immunol. 2009 Jul 15;183(2):1005-12
references: 19542370
references: J Immunol. 2005 May 1;174(9):5462-71
references: 15843544
references: Ann Intern Med. 1989 Aug 1;111(3):223-31
references: 2546472
references: Am J Respir Crit Care Med. 2004 Aug 15;170(4):408-13
references: 15117741
references: Nat Immunol. 2009 Mar;10(3):314-24
references: 19182808
references: Clin Exp Immunol. 2003 Nov;134(2):202-9
references: 14616778
references: J Exp Med. 1988 Apr 1;167(4):1350-63
references: 2965736
references: Infect Immun. 1997 Dec;65(12):5052-6
references: 9393795
references: Infect Immun. 2007 Jun;75(6):3055-61
references: 17403873
references: J Immunol. 2003 Aug 1;171(3):1423-30
references: 12874234
references: J Clin Invest. 1999 Jun;103(12):1707-17
references: 10377177
references: Am J Pathol. 2010 Jun;176(6):2806-18
references: 20395428
references: J Exp Med. 2010 Dec 20;207(13):2907-19
references: 21149550
references: J Infect Dis. 1996 Apr;173(4):1034-7
references: 8603947
references: J Clin Invest. 1992 Aug;90(2):673-8
references: 1353767
references: Nature. 1996 Jul 11;382(6587):174-7
references: 8700209
references: J Immunol. 2006 Nov 1;177(9):6215-26
references: 17056551
references: AIDS. 2003 Jan 3;17(1):73-80
references: 12478071
references: Infect Immun. 1993 Nov;61(11):4703-9
references: 8406869
references: BMC Infect Dis. 2008 Sep 16;8:118
references: 18796158
references: J Clin Microbiol. 2009 Nov;47(11):3773-6
references: 19759224
references: Nat Immunol. 2011 Dec 04;13(1):58-66
references: 22138715
references: Front Biosci. 2008 Jan 01;13:453-61
references: 17981560
references: Infect Immun. 2008 May;76(5):2130-7
references: 18332204
references: Immunity. 2008 Nov 14;29(5):679-90
references: 18993086
references: J Infect Dis. 2000 Jun;181(6):2011-7
references: 10837183
references: J Immunol. 2003 Jan 15;170(2):1002-9
references: 12517967
references: Infect Immun. 2009 May;77(5):1790-7
references: 19255189
references: J Clin Invest. 1997 May 1;99(9):2110-7
references: 9151783
references: J Immunol. 2008 May 15;180(10):6656-62
references: 18453585
references: J Immunol. 2007 Apr 15;178(8):4901-7
references: 17404271