Evolution of the human CD4+ T cell response to Epstein-Barr virus infection - analysis of systemic and local immune responses

Meckiff, Benjamin James (2021). Evolution of the human CD4+ T cell response to Epstein-Barr virus infection - analysis of systemic and local immune responses. University of Birmingham. Ph.D.

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Abstract

CD4+ T cells are essential for overall control of human virus infections, yet their multiple roles remain ill-defined at the single cell level, and most studies have focused solely on analysis of those present in the circulation. Using Epstein-Barr virus (EBV)-specific human leukocyte antigen (HLA) class II tetramers, we have studied the circulating functional and clonal evolution of circulating antigen-specific CD4+ T cell responses
during infection and analysed the CD4+ T cell response at the site of viral replication. We show that primary EBV infection, elicits an acute expansion of oligoclonal antigenspecific T helper-1 (TH1)-like CD4+ T cell populations in the blood that are armed with cytotoxic proteins and can respond immediately ex vivo to challenge with virus-infected B cells. Over time as the primary response contracts, we find that the resultant memory populations show (i) a marked decrease in cells expressing cytotoxic and activation markers, but (ii) increased TCR diversity as new clonotypes join those originally present, and (iii) increased cytokine polyfunctionality. Importantly, the cytotoxic CD4+ T cells responding to acute primary infection differed in their transcriptional program to the classically described CD4-CTLs that accumulate during chronic viral infections.
Moreover, we show that EBV infection seeds populations of tissue resident EBV-specific CD4+ T cells in the tonsil. These EBV-specific TRM which expresses cytotoxic proteins, are preferentially retained in the T cell zone and B cell follicles of the tonsils. These findings imply an important effector role for CD4-CTLs in acute EBV infection and at the site of EBV replication, emphasising the need to harness their potential in herpesvirus vaccine design.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):