Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4+ T Cells.

Benjamin J Meckiff,David A Price,Kristin Ladell,Alison M Leese,James E Mclaren,Gordon B Ryan,Eddie A James,Heather M Long

doi:10.4049/jimmunol.1900377

Benjamin J Meckiff, David A Price + Show 6 more

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https://doi.org/10.4049/jimmunol.1900377

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CD4+ T cells are essential for immune protection against viruses, yet their multiple roles remain ill-defined at the single-cell level in humans. Using HLA class II tetramers, we studied the functional properties and clonotypic architecture of EBV-specific CD4+ T cells in patients with infectious mononucleosis, a symptomatic manifestation of primary EBV infection, and in long-term healthy carriers of EBV. We found that primary infection elicited oligoclonal expansions of TH1-like EBV-specific CD4+ T cells armed with cytotoxic proteins that responded immediately ex vivo to challenge with EBV-infected B cells. Importantly, these acutely generated cytotoxic CD4+ T cells were highly activated and transcriptionally distinct from classically described cytotoxic CD4+ memory T cells that accumulate during other persistent viral infections, including CMV and HIV. In contrast, EBV-specific memory CD4+ T cells displayed increased cytokine polyfunctionality but lacked cytotoxic activity. These findings suggested an important effector role for acutely generated cytotoxic CD4+ T cells that could potentially be harnessed to improve the efficacy of vaccines against EBV.

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To profile the functional capabilities of EBV-specific memory CD4+ T cells in healthy virus carriers directly ex vivo, we employed a panel of pMHCII tetramers (Table I) optimized in our previous work [22]
21.4% of pMHCII tetramer+ cells made none of these cytokines, most likely reflecting those residing in the TCM component, which is less responsive ex vivo [2, 16, 22]
We used pMHCII tetramers to investigate the functional profile of EBV-specific CD4+ T cells induced by primary infection, in which we have previously shown expansions of effector CD4+ T cells (CD45RA+, CCR72, CD62L2) specific for a broad range of EBV Ags, with frequencies up to 10-fold greater than those detected in healthy carriers [22]

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Relatively low percentages of total CD4+ T cells (typically ,5%) expressed Perf/GzmB in healthy carriers (Fig. 3A, 3G), and this was the case for the EBV-specific memory CD4+ T cells. In all cases, much higher frequencies of EBV-specific CD4+ T cells expressed Perf/GzmB in patients with acute IM compared with healthy carriers (mean 56.2% versus mean 2.7%, respectively, p , 0.0001).

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