This project is a comprehensive look into the CD4 T cell response to human herpesvirus 6 (HHV-6), an emergent / re-emergent human pathogen. In most people infection in childhood resolves uneventfully to a chronic life-long infection held in check by cellular immune responses. However, viral reactivation after immunosuppression can cause serious illness, neurological complications, and even death, and is an important complication following organ transplantation.
One aim of the project is to characterize memory T cell responses to this chronic infection, and compare them to responses to acute infection. CD4 and CDS T cell responses to HHV-6 will be characterized in healthy immune donors and also in kidney transplant recipients experiencing viral reactivation. A possible role for IL-10 in regulating these responses will be investigated. These analysis will involve ex vivo analysis of, peripheral blood and primary cell lines, using functional assays and newly-developed class II MHC oligomers, and will be pursued in collaboration with project 2, which is investigating analogous CD4 T cell functional subsets in mice.
A second aim of the project is to understand the role of NK cells in regulating T cell responses to HHV-6. Preliminary data indicate that NK populations present in peripheral blood regulate CD4 T cells responding to HHV-6. Several mechanistic hypotheses will be explored using ex vivo analysis of human peripheral blood and primary cell lines. This work will be pursued in collaboration with project 1, which is investigating similar NK phenomenon in other systems.
A third aim of the project is to investigate and functionally characterize CD4 T cell responses to HHV-6 that are cross-reactive with other viruses. Several recently identified HHV-6 T cell epitopes are similar to those from other common viral infections. Based on principles established in previous work on CDS cross-reactivity patterns, we predict that the HHV-6 specific CD4 T cell response can recognize heterologous infection by other viruses including EBV, CMV, and lAV. This prediction will be tested using ex vivo analysis of human peripheral blood and primary cell lines, and biochemical and structural analysis of MHC and TCR proteins.
This aim will be pursued in collaboration with project 3.
Human herpesvirus 6 infects most people early in life causing a mild childhood illness that remains present as a life-long chronic infection but which can reactivate after immune suppression to cause serious medical consequences. This project will investigate HHV-6 immune responses in healthy people controlling the virus and in immunosuppressed transplantation recipients in whom the virus has reactivated, to better understand immune control of HHV-6 and to help development of clinically useful diagnostic tools.
|Strutt, T M; Dhume, K; Finn, C M et al. (2018) IL-15 supports the generation of protective lung-resident memory CD4 T cells. Mucosal Immunol 11:668-680|
|Devarajan, Priyadharshini; Jones, Michael C; Kugler-Umana, Olivia et al. (2018) Pathogen Recognition by CD4 Effectors Drives Key Effector and Most Memory Cell Generation Against Respiratory Virus. Front Immunol 9:596|
|Hatfield, Steven D; Daniels, Keith A; O'Donnell, Carey L et al. (2018) Weak vaccinia virus-induced NK cell regulation of CD4 T cells is associated with reduced NK cell differentiation and cytolytic activity. Virology 519:131-144|
|Becerra-Artiles, Aniuska; Santoro, Tessa; Stern, Lawrence J (2018) Evaluation of a method to measure HHV-6B infection in vitro based on cell size. Virol J 15:4|
|Marshall, Nikki B; Vong, Allen M; Devarajan, Priyadharshini et al. (2017) NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection. J Immunol 198:1142-1155|
|Blevins, Sydney; Huseby, Eric S (2017) Killer T cells with a beta-flavi(r) for dengue. Nat Immunol 18:1186-1188|
|Antunes, Dinler A; Rigo, Maurício M; Freitas, Martiela V et al. (2017) Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy. Front Immunol 8:1210|
|Shin, Hyun Mu; Kapoor, Varun N; Kim, Gwanghun et al. (2017) Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory. PLoS Pathog 13:e1006544|
|Song, InYoung; Gil, Anna; Mishra, Rabinarayan et al. (2017) Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope. Nat Struct Mol Biol 24:395-406|
|Watkin, Levi B; Mishra, Rabinarayan; Gil, Anna et al. (2017) Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion. J Allergy Clin Immunol 140:1206-1210|
Showing the most recent 10 out of 41 publications