Study Unveils New Immune Cell Precursor Leads to Improved HIV Vaccine
In a new study, researchers at the La Jolla Institute for Allergy and Immunology (LJI) have discovered how a type of killer T cell develops, opening the door to improved vaccine design for diseases, such as HIV and hep C.
The team used single-cell transcriptome analysis to identify a hitherto unknown precursor for a poorly understood subgroup of killer T cells that is primarily found in humans with chronic viral infections. Their detailed analysis of the entirety of transcribed genes in more than 9,000 individual cells also revealed an unprecedented level of heterogeneity.
“Continually evolving genomic tools and single cell analysis technologies are revolutionizing our understanding of the human immune system in health and disease,” says Pandurangan Vijayanand, M.D., Ph.D., Associate Professor and William K. Bowes Jr. Distinguished Professor at LJI who led the study. “But this is just the beginning of the genomic journey. By applying these tools in relevant diseases and cell types we are changing our understanding of the biology of human immune cells.”
Based on cell surface markers known as CD4 and CD8, T cells generally fall into two broad categories: CD4-positive helper T cells
, which help activate other immune cells and CD8-positive cytotoxic T cells, which kill cells that are cancerous or infected with viruses. Under certain circumstances, however, a portion of helper T cells turns into cytotoxic T cells (CD4-CTLs). CD4 CTLs were originally reported in humans with chronic viral infections such as human cytomegalovirus (CMV), HIV, dengue virus and hepatitis C virus but have also been linked to protective antitumor immune responses, especially in virally induced tumors.The researchers detail how CD4 cytotoxic T cells arise in humans and facilitate improved vaccine design to protect against chronic viral infections.
“The observed increase in the ratio of cytotoxic CD4 T cells to CD4 helper T cells indicates that they are an important component of the protective immune response to viral infections and that their induction should be an important marker for successful vaccinations against certain viral diseases,” says postdoctoral researcher and first author Veena Patil, Ph.D. “But we really didn’t know enough about their molecular profile and the mechanisms that drive their differentiation and maintenance.”
The team started out by analyzing thousands of individual CD4-CTLs isolated from peripheral blood from donors using single cell RNA sequencing, which can define different cell types and subtypes by revealing differences in the transcripts produced by individual cells.
Their analysis uncovered remarkable heterogeneity between individual cells but also within individuals. “It is probably the result of the diverse nature of infections and timing of viral exposures coupled with genetic diversity among our study subjects,” she says.
Vijayanand and his team were also able to identify a subset of CD4-CTLs precursors that potentially give rise to fully fledged CD4 CTLs in human. “Understanding the origins and biology of potentially long-lived CD4-CTL precursors may pave the way for developing strategies to boost durable CD4-CTL immune responses after vaccination against viral infections and cancer,” the authors write in their paper.
