title: High viral burden restricts short-lived effector cell number at late times postinfection through increased natural regulatory T cell expansion.
abstract: Generating and maintaining a robust CD8(+) T cell response in the face of high viral burden is vital for host survival. Further, balancing the differentiation of effectors along the memory precursor effector cell pathway versus the short-lived effector cell (SLEC) pathway may be critical in controlling the outcome of virus infection with regard to clearance and establishing protection. Although recent studies have identified several factors that have the capacity to regulate effector CD8(+) T cell differentiation-for example, inflammatory cytokines-we are far from a complete understanding of how cells choose the memory precursor effector cell versus SLEC fate following infection. In this study, we have modulated the infectious dose of the poxvirus vaccinia virus as an approach to modulate the environment present during activation and expansion of virus-specific effector cells. Surprisingly, in the face of a high virus burden, the number of SLECs was decreased. This decrease was the result of increased natural regulatory T cells (Tregs) generated by high viral burden, as depletion of these cells restored SLECs. Our data suggest Treg modulation of differentiation occurs via competition for IL-2 during the late expansion period, as opposed to the time of T cell priming. These findings support a novel model wherein modulation of the Treg response as a result of high viral burden regulates late-stage SLEC number.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Amoah
authors.forename: Beth C
authors.initials: BC
authors.lastname: Holbrook
authors.forename: Rama D
authors.initials: RD
authors.lastname: Yammani
authors.forename: Martha A
authors.initials: MA
authors.lastname: Alexander-Miller
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D060908:CTLA-4 Antigen / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic; D050799:STAT5 Transcription Factor; D050378:T-Lymphocytes, Regulatory / Q000821:virology; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D019562:Viral Load
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D050799:STAT5 Transcription Factor; C106544:Tnfrsf18 protein, mouse; D018664:Interleukin-12; D053148:Caspase 3