When surveying immunological research of the past decade or two, there are many cases in which specific subsets of adaptive immune system cell populations can be identified as problematic or actively harmful in older individuals. This goes beyond the obvious candidates such as senescent and exhausted T cells, and includes such things as the inflammatory T regulatory cells that emerge following heart injury. Researchers here describe another apparently harmful population of T cells associated with a failed influenza vaccine response. Would a targeted removal of these cells help? Since targeted removal of problem immune cells has helped in other circumstances and other studies, it sounds worth a try.
Decline in immune function has been well described in the setting of physiologic aging manifesting as impaired vaccine responses and diminution of antibody (Ab)-secreting cells with reduced numbers of lymph node germinal centers (GCs). CD4 T cells provide help to antigen-primed B cells to undergo proliferation, isotype switching, and somatic hypermutation resulting in the generation of long-lived plasma cells and memory B cells (MBCs).
This help is mediated by a specialized CD4 T-cell subset known as T follicular helper (Tfh) cells, characterized by the expression of CXCR5, which is required for the cells to migrate to the GC. We and others have described a circulating counterpart of CXCR5+ Tfh cells known as peripheral Tfh (pTfh) cells that are easily accessible from patient blood samples and are able to induce B cell differentiation. Studies in healthy adults have documented the importance of pTfh expansion at day 7 or day 28 post vaccination for their association with influenza vaccine response.
In order to understand the Ab response to influenza vaccine and the effect of aging with or without HIV infection, we conducted the present study in young and old HIV+ and HIV-uninfected healthy control [HC] participants who had already been classified as vaccine responders (VRs) and vaccine nonresponders (VNRs) based on their serologic responses to seasonal influenza vaccine. We focused on antigen-specific pTfh (Ag.pTfh). In this study, ex vivo quantitative and qualitative assessment of Ag.pTfh revealed key features of Ag.pTfh that favored vaccine responsiveness. In VRs, magnitude of response was impacted by both quality and quantity of Ag.pTfh cells, and these were compromised in old age in HCs and in young and old HIV+ individuals. In VNRs, in contrast, Ag.pTfh were heavily weighted towards an inflammatory phenotype irrespective of age or HIV status.
Our findings demonstrate that dysfunctional Ag.pTfh cells with an altered IL-21/IL-2 axis contribute to inadequate vaccine responses. Approaches for targeting inflammation or expanding functional Tfh may improve vaccine responses in aging and those aging with HIV infection.