Proteome-wide analysis of T-cell response to BK polyomavirus in healthy virus carriers and kidney transplant recipients reveals a unique transcriptional and functional profile

George R Ambalathingal; Ross S Francis; Dillon Corvino; Sriganesh Srihari; Blake T Aftab; Corey Smith; Rajiv Khanna

doi:10.1002/cti2.1102

Proteome-wide analysis of T-cell response to BK polyomavirus in healthy virus carriers and kidney transplant recipients reveals a unique transcriptional and functional profile

Clin Transl Immunology. 2020 Jan 14;9(1):e01102. doi: 10.1002/cti2.1102. eCollection 2020.

Authors

George R Ambalathingal¹, Ross S Francis^{2

3}, Dillon Corvino^{1

3}, Sriganesh Srihari¹, Blake T Aftab⁴, Corey Smith¹, Rajiv Khanna^{1

3}

Affiliations

¹ QIMR Berghofer Centre for Immunotherapy and Vaccine Development Tumour Immunology Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
² Department of Nephrology Princess Alexandra Hospital Woolloongabba QLD Australia.
³ School of Medicine University of Queensland Brisbane QLD Australia.
⁴ Department of Preclinical and Translational Sciences Atara Biotherapeutics Los Angeles CA USA.

Abstract

Objectives: Cellular immunity against BK polyomavirus (BKV)-encoded antigens plays a crucial role in long-term protection against virus-associated pathogenesis in transplant recipients. However, in-depth understanding on dynamics of these cellular immune responses is required to develop better immune monitoring and immunotherapeutic strategies.

Methods: Here, we have conducted a proteome-wide analysis of BKV-specific T-cell responses in a cohort of 53 healthy individuals and 26 kidney transplant recipients to delineate the functional and transcriptional profile of these effector cells and compared these characteristics to T cells directed against cytomegalovirus, which is also known to cause significant morbidity in transplant recipients.

Results: Profiling of BKV-specific CD4⁺ and CD8⁺ T cells revealed that kidney transplant recipients with high levels of circulating viraemia showed significantly reduced T-cell reactivity against large T and/or small T antigens when compared to healthy donors. Interestingly, T cells specific for these antigens showed strong cross-recognition to orthologous JC virus (JCV) peptides, including those exhibiting varying degrees of sequence identity. Ex vivo functional and phenotypic characterisation revealed that the majority of BKV-specific T cells from renal transplant recipients expressed low levels of the key transcriptional regulators T-bet and eomesodermin, which was coincident with undetectable expression of granzyme B and perforin. However, in vitro stimulation of T cells with BKV epitopes selectively enhanced the expression of T-bet, granzyme B and cellular trafficking molecules (CCR4, CD49d and CD103) with minimal change in eomesodermin and perforin.

Conclusions: These observations provide an important platform for the future development of immune monitoring and adoptive T-cell therapy strategies for BKV-associated diseases in transplant recipients, which may also be exploited for similar therapeutic value in JCV-associated clinical complications.

Keywords: T cells; adaptive immunity; cellular immunity; immunology; immunotherapy; infectious diseases; innate immune cells; lymphocytes; viral infection.