Immune Responses to Persistent or Recurrent Antigens: Implications for Immunological Memory and Immunotherapy

Abstract

Immunological memory is considered the hallmark of the adaptive immune response, which is essential for long-term protection against infection throughout life. From the perspective of adaptive immunity, clonally expanded antigen-specific lymphocytes accumulate within the immunological memory repertoire to confer protection upon re-encounter with persistent and/or recurrent pathogens. Furthermore, memory cells often respond more rapidly and effectively following antigen encounter than naïve precursors do. Recent increasing evidence suggests that immunological memory can also be a feature of innate immune cells. Innate immunological memory has been frequently described as a trained potentiation of anti-pathogen responses upon re-infection and is exquisitely coordinated by transient genetic and transcriptional changes (e.g., epigenetic reprogramming) that alter the functions of innate immune cells, such as macrophages, monocytes, dendritic cells and NK cells.

Under physiological conditions, immunological memory responses are known to undergo alterations throughout our lifespan and can be differentially impacted during the process of aging. However, in conditions such as chronic inflammation (e.g., autoimmune disease and cancer) and in chronic infection due to the presence of persistent pathogen(s), abnormal alterations in immunological memory responses can occur, leading to memory cell exhaustion. This renders vulnerable individuals, such as the elderly, patients suffering from cancer, and transplant recipients at higher risk of infection. Severe infectious conditions, such as sepsis, are also known to affect the metabolic profile and function of immune cells, somehow speeding up the exhaustion of immunological memory.

This deterioration of the immune response is characterized by genetic / epigenetic alterations in immune cells that are driven by chronic or repeated exposure to antigens derived from: (i) persistent or recurrent pathogens (e.g. virus, bacteria and fungi); (ii) self-tissues and (iii) cancer cells. In adaptive immunity, constant stimulation by persistent antigens leads to a disproportionate accumulation of antigen-experienced or memory-phenotype lymphocytes. These phenomena are associated with (i) a decreased diversity of antigen-receptor repertoires and (ii) alterations in signal transduction and cell differentiation processes, subsequently leading to impaired antibody production and/or altered T cell responses, including exhaustion. Similarly, persistent antigens and PAMPs are also known to cause alterations in innate immune cells which can be complex.

Therefore, immune memory responses are affected by cellular exposure to persistent/recurrent antigenic challenges (including PAMPs/DAMPs), ultimately resulting in (i) the development of chronic inflammation, (ii) dampened responses to vaccination and (iii) the development of disease, all of which negatively impact on human longevity.