In this project we examine how immunological memory formed during one infection is protected from erasure in the face of repeated subsequent infections by multiple unrelated pathogens. This is significant because stable memory is essential for immunizations to successfully confer lifelong protective immunity. Understanding this mechanism will allow us to improve vaccines that otherwise require frequent boosting and even develop new ones for diseases such as malaria. Although cytokines such as IL7 and IL-15 maintain the absolute size of the memory T cell pool in the immune system, the pathways ensuring that the population includes adequate representation of all the previous experiences, is not known. Based on our recent work, we hypothesize that the maintenance of a diverse CD4+ memory repertoire requires trophic interactions of memory T cells with endogenous sub- threshold ligands (STLs). STLs are distinct peptide-MHC complexes that are too weak to stimulate conventional T cell activation. Since only a small proportion of memory cells engage a particular STL, competition for survival is limited to these small colonies of T cells. The significance of this mechanism is that it avoids a much broader repertoire loss that might happen if the competition was more widespread. We have generated unique reagents and developed methodologies to test this innovative hypothesis using two major independent and complimentary aims. 1. Establish how TCR-specificity determines which T cells can compete during memory maintenance, using recently identified TCRs that either share antigen-specificity or STL-specificity. We will examine the cellular mechanisms for such competition and establish the range of impact it has on a polyclonal repertoire of T cells. 2. Using sequential infections with Plasmodium, Influenza and Toxoplasma, evaluate how pre-existing memory T cells can be destabilized by the response to a new infection. We will also explore how STL- treatment can help restore the stability of memory T cells in this context. On completion, we expect to offer a novel understanding of CD4+ memory maintenance and suggest strategies to improve memory T cell survival during adoptive therapies and vaccinations. The converse strategies can help decrease the frequency of pathogenic T cells during autoimmunity and transplantation.
This project examines how the immune system remembers the strategy that helped it repel an earlier infection, even after it has battled many other unrelated pathogens. This memory is also the basis of successful vaccinations. Our studies will help improve the duration of protection from existing vaccines and design new ones for diseases such as Malaria based on a new paradigm for improving T cell numbers in the body, by using very specific peptides. These peptides can also help augment the efficacy of adoptive transfer therapies for tumor and infectious disease. Conversely, inhibitory drugs targeting these interactions can reduce T cell mediated autoimmune disease and help improve the body's tolerance to transplants.
| Abdi, Kaveh; Chen, Tsute; Klein, Brian A et al. (2017) Mechanisms by which Porphyromonas gingivalis evades innate immunity. PLoS One 12:e0182164 |
| Chuang, Eleanore; Augustine, Marilyn; Jung, Matthew et al. (2017) Density dependent re-tuning of autoreactive T cells alleviates their pathogenicity in a lymphopenic environment. Immunol Lett 192:61-71 |
| Singh, Nevil J (2016) Self-reactivity as the necessary cost of maintaining a diverse memory T-cell repertoire. Pathog Dis 74: |
| Abdi, Kaveh; Singh, Nevil J (2015) Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines. Cytokine 76:53-7 |
