Upregulation of Multiple CD8(+) T Cell Exhaustion Pathways Is Associated with Recurrent Ocular Herpes Simplex Virus Type 1 Infection
JOURNAL OF IMMUNOLOGY
Authors: Coulon, Pierre-Gregoire; Roy, Soumyabrata; Prakash, Swayam; Srivastava, Ruchi; Dhanushkodi, Nisha; Salazar, Stephanie; Amezquita, Cassandra; Lan Nguyen; Vahed, Hawa; Nguyen, Angela M.; Warsi, Wasay; Ye, Caitlin; Carlos-Cruz, Edgar A.; Mai, Uyen T.; BenMohamed, Lbachir
Abstract
A large proportion of the world's population harbors latent HSV type 1 (HSV-1). Cross-talk between antiviral CD8(+) T cells and HSV-1 appear to control latency/reactivation cycles. We found that compared with healthy asymptomatic individuals, in symptomatic (SYMP) patients, the CD8(+) T cells with the same HLA-A*0201-restricted HSV-1 epitope specificities expressed multiple genes and proteins associated to major T cell exhaustion pathways and were dysfunctional. Blockade of immune checkpoints with anti-LAG-3 and anti-PD-1 antagonist mAbs synergistically restored the frequency and function of antiviral CD8(+) T cells, both 1) ex vivo, in SYMP individuals and SYMP HLA-A*0201 transgenic mice; and 2) in vivo in HSV-1-infected SYMP HLA-A*0201 transgenic mice. This was associated with a significant reduction in virus reactivation and recurrent ocular herpetic disease. These findings confirm antiviral CD8(+) T cell exhaustion during SYMP herpes infection and pave the way to targeting immune checkpoints to combat recurrent ocular herpes.
Genetic diversity of HLA system in two populations from Oaxaca, Mexico: Oaxaca city and rural Oaxaca
HUMAN IMMUNOLOGY
Authors: Hernandez-Hernandez, Ofelia; Iraiz Hernandez-Zaragoza, Diana; Barquera, Rodrigo; Warinner, Christina; Lopez-Gil, Concepcion; Arrieta-Bolanos, Esteban; Clayton, Stephen; Bravo-Acevedo, Alicia; del Rocio Ramos-de la Cruz, Flor; Mendez-Mani, Patricia; de los Angeles Pavon-Vargas, Maria; Zuniga, Joaquin; Yunis, Edmond J.; Bekker-Mendez, Carolina; Granados, Julio
Abstract
We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 636 Mexicans from the state of Oaxaca living in the city of Oaxaca (N = 151) and rural communities (N = 485), to obtain information regarding allelic and haplotypic frequencies. We found that the 13 most frequent haplotypes in Oaxaca are all of putative Native American origin. Admixture estimates revealed that the main genetic components in the state of Oaxaca are Native American (73.12 +/- 2.77% by ML; 61.52% of Native American haplotypes) and European (17.36 +/- 2.07% by ML; 20.69% of European haplotypes), and a relatively high African genetic component (9.52 +/- 0.88% by ML; 8.94% of African haplotypes).