Immunological memory is the basis of protective immunity provided by vaccines and previous infections. Immunological memory can develop from multiple branches of the adaptive immune system, including ...CD4 T cells, CD8 T cells, B cells, and long‐lasting antibody responses. Extraordinary progress has been made in understanding memory to SARS‐CoV‐2 infection and COVID‐19 vaccines, addressing development; quantitative and qualitative features of different cellular and anatomical compartments; and durability of each cellular component and antibodies. Given the sophistication of the measurements; the size of the human studies; the use of longitudinal samples and cross‐sectional studies; and head‐to‐head comparisons between infection and vaccines or between multiple vaccines, the understanding of immune memory for 1 year to SARS‐CoV‐2 infection and vaccines already supersedes that of any other acute infectious disease. This knowledge may help inform public policies regarding COVID‐19 and COVID‐19 vaccines, as well as the scientific development of future vaccines against SARS‐CoV‐2 and other diseases.
Helping B cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage-defining transcription factor for T follicular helper ...(Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers (the microanatomical sites of B cell mutation and antibody affinity maturation) and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years, particularly regarding their roles in a surprising range of diseases. Advances in the understanding of Tfh cell differentiation and function are discussed, as are the understanding of Tfh cells in infectious diseases, vaccines, autoimmune diseases, allergies, atherosclerosis, organ transplants, and cancer. This includes discussion of Tfh cells in the human immune system. Based on the discoveries to date, the next decade of Tfh research surely holds many more surprises.
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Tfh cells are the CD4+ T cells specialized for helping B cells. Bcl6 was identified as the Tfh lineage-defining transcription factor 10 years ago. Crotty reviews the extensive progress made in understanding Tfh cells since then, including surprising roles of Tfh cells in a range of diseases.
T‐cell help to B cells is a fundamental aspect of adaptive immunity and the generation of B‐cell memory (memory B cells and plasma cells). Follicular helper CD4+ T (Tfh) cells are the specialized ...providers of B‐cell help, and Tfh cells depend on Bcl6 for their differentiation. This review discusses Tfh cell functions, transcription factors, and induction signals, with particular focus on the richness of the underlying biology and assessing the simplicity or complexity of each of these processes.
The majority of all vaccines work by inducing protective antibody responses. The mechanisms by which the B cells responsible for producing protective antibodies are elicited to respond are not well ...understood. Interclonal B cell competition to complex antigens, particularly in germinal centers, has emerged as an important hurdle in designing effective vaccines. This review will focus on recent advances in understanding the roles of B cell precursor frequency, B cell receptor affinity for antigen, antigen avidity, and other factors that can substantially alter the outcomes of B cell responses to complex antigens. Understanding the interdependence of these fundamental factors that affect B cell responses can inform current vaccine design efforts for pathogens with complex proteins as candidate immunogens such as HIV, influenza, and coronaviruses.
Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high-affinity ...antibodies and memory B cells. Tfh cell differentiation is a multistage, multifactorial process involving B cell lymphoma 6 (Bcl6) and other transcription factors. This article reviews understanding of Tfh cell biology, including their differentiation, migration, transcriptional regulation, and B cell help functions. Tfh cells are critical components of many protective immune responses against pathogens. As such, there is strong interest in harnessing Tfh cells to improve vaccination strategies. Tfh cells also have roles in a range of other diseases, particularly autoimmune diseases. Overall, there have been dramatic advances in this young field, but there is much to be learned about Tfh cell biology in the interest of applying that knowledge to biomedical needs.
In celebration of the 50th anniversary of the discovery of B cells, I take a look back at the history of T cell help to B cells, which was discovered 47 years ago. In addition, I summarize and ...categorize the distinct molecules that are expressed by CD4(+) T cells that constitute 'help' to B cells, and particularly the molecules expressed by T follicular helper (TFH) cells, which are the specialized providers of help to B cells.
Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the ...COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4
T cells and CD8
T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4
T cell, and CD8
T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and ...CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.
The adaptive immune system is crucial for controlling viral infection, but the kinetics and magnitude of the roles of its various components differ across viral infections. Review the emerging data on the roles of B cells, CD4+ T cells, and CD8+ T cells in SARS-CoV-2 infection.
Bcl6 is required for CD4 T cell differentiation into T follicular helper cells (Tfh). In this study, we examined the role of IL-6 in early processes of in vivo Tfh differentiation, because the timing ...and mechanism of action of IL-6 in Tfh differentiation have been controversial in vivo. We found that early Bcl6(+)CXCR5(+) Tfh differentiation was severely impaired in the absence of IL-6; however, STAT3 deficiency failed to recapitulate that defect. IL-6R signaling activates the transcription factor STAT1 specifically in CD4 T cells. Strikingly, we found that STAT1 activity was required for Bcl6 induction and early Tfh differentiation in vivo. IL-6 mediated STAT3 activation is important for downregulation of IL-2Rα to limit Th1 cell differentiation in an acute viral infection. Thus, IL-6 signaling is a major early inducer of the Tfh differentiation program unexpectedly mediated by both STAT3 and STAT1 transcription factors.
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