Increased Immune Response Variability during Simultaneous Viral Coinfection Leads to Unpredictability in CD8 T Cell Immunity and Pathogenesis.
T cell memory is usually studied in the context of infection with a single pathogen in naive mice, but how memory develops during a coinfection with two pathogens, as frequently occurs in nature or after vaccination, is far less studied. Here, we questioned how the competition between immune responses to two viruses in the same naive host would influence the development of CD8 T cell memory and subsequent disease outcome upon challenge. Using two different models of coinfection, including the well-studied lymphocytic choriomeningitis (LCMV) and Pichinde (PICV) viruses, several differences were observed within the CD8 T cell responses to either virus. Compared to single-virus infection, coinfection resulted in substantial variation among mice in the size of epitope-specific T cell responses to each virus. Some mice had an overall reduced number of virus-specific cells to either one of the viruses, and other mice developed an immunodominant response to a normally subdominant, cross-reactive epitope (nucleoprotein residues 205 to 212, or NP205). These changes led to decreased protective immunity and enhanced pathology in some mice upon challenge with either of the original coinfecting viruses. In mice with PICV-dominant responses, during a high-dose challenge with LCMV clone 13, increased immunopathology was associated with a reduced number of LCMV-specific effector memory CD8 T cells. In mice with dominant cross-reactive memory responses, during challenge with PICV increased immunopathology was directly associated with these cross-reactive NP205-specific CD8 memory cells. In conclusion, the inherent competition between two simultaneous immune responses results in significant alterations in T cell immunity and subsequent disease outcome upon reexposure.


OBJECTIVE
Combination vaccines and simultaneous administration of vaccines are necessary to accommodate required immunizations and maintain vaccination rates. Antibody responses generally correlate with protection and vaccine efficacy. However, live attenuated vaccines also induce strong CD8 T cell responses, and the impact of these cells on subsequent immunity, whether beneficial or detrimental, has seldom been studied, in part due to the lack of known T cell epitopes to vaccine viruses. We questioned if the inherent increased competition and stochasticity between two immune responses during a simultaneous coinfection would significantly alter CD8 T cell memory in a mouse model where CD8 T cell epitopes are clearly defined. We show that some of the coinfected mice have sufficiently altered memory T cell responses that they have decreased protection and enhanced immunopathology when reexposed to one of the two viruses. These data suggest that a better understanding of human T cell responses to vaccines is needed to optimize immunization strategies.
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Laurie L
LL
Kenney
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
Markus
M
Cornberg
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Alex T
AT
Chen
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
Sebastien
S
Emonet
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
Juan Carlos
JC
de la Torre
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Liisa.Selin@umassmed.edu.
Liisa K
LK
Selin
D000704:Analysis of Variance; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060085:Coinfection / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017385:Sequence Homology; D013045:Species Specificity