Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Erica Bizzell¹  Jonathan Kevin Sia¹  Melanie Quezada¹  Ana Enriquez¹  Maria Georgieva¹  Jyothi Rengarajan¹ 

[1] Emory Vaccine Center, Emory University;Department of Epidemiology, Harvard T. H. Chan School of Public Health;Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine

关键词: immune evasion;    immunogenicity;    tuberculosis;    vaccine;   

DOI  :  10.1002/JLB.4A0917-363RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovis Bacille Calmette-Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen-specific CD4 T cell responses that limit the immunogenicity of BCG.We generated a strain of BCG lacking hip1 (BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1-infected DCs were more effective at driving the production of IFN-? and IL-17 from antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge.

【 授权许可】

CC BY