Cell specific roles of CD153 and CD30 in regulation of immune responses

ABSTRACT Declining immune function in the elderly leads to increased risk and severity of infection and impaired responses to vaccination. Our and others prior work have shown that control of immune responses in aged individuals is complex. Although immune responses to immunization are generated in the elderly, they are tempered by impaired intrinsic function of many immune cell types, accrual of immune suppressive and senescent cells, which results in inappropriate localization and function of B and T cells. Strikingly however, our and other’s data also show that age-related, decreased immune responsiveness to immunization is reversible by enhancing stimulatory signals or reducing inhibitory signals. Thus, understanding the mechanism(s) regulating age-related immune responses is critical to unlocking the potential for reinvigorating immune responses in aging. Recent data from our extensive single cell genomics analysis of aged memory CD4+ T cells show that CD153 is one of the most highly expressed genes in aged T follicular helper (Tfh) cells. Although the general consensus is that CD153 expression on CD4+ T cells is critical for its function this remains to be rigorously tested and the cell- specific role of CD30 remains controversial. Some data show both stimulatory and suppressive roles of CD30 on B cells; while other data shows a critical immune stimulatory role of CD30 on T cells. Thus, the cell-specific functions of CD153 and CD30 have yet to be cleanly defined in vivo. To begin to determine the role of CD153/CD30 signaling in regulation of immune responses in aged mice, we blocked CD153/CD30 signaling in aged, NP-KLH immunized mice using a non-depleting, blocking antibody. Strikingly, we saw a significant decrease in NP-specific (NP-sp.) IgG1 in the serum as well as a dramatic loss of NP-sp. GC B cells after CD153/CD30 blockade. However, we still lack understanding of the underlying biology of CD153/CD30 interactions. Based on robust preliminary data, we hypothesize that: CD4+ T cell expression of CD153 is sustained by IL-6 and is required to signal to CD30 expression of B cells; these interactions are critical to promote antibody responses in aged mice. We generated mice with conditional alleles for CD153 (CD153fl/fl) and CD30 (CD30fl/fl), and will use them to (i) define the temporal role of CD153 on CD4+ T cells in controlling antibody responses in aged mice; and (ii) define the role of CD30 and its potential for regulating B cell responses in aged mice. Overall Impact: This research fits the R21 definition of “high-risk” as the cell-specific roles of CD153 and CD30, may not be clear-cut. It is also ”high-reward” because, if successful, we will fill important gaps in knowledge regarding the cell-specific and temporal roles of CD30 and CD153 in control of B cell responses in aged mice. Further, it will enable future mechanistic studies to determine the potential for manipulating this axis to boost B cell responses in the aged.