Adaptive Immune Responses: Memory Cells

• Diversity in T-cell and B-cell receptors enables the adaptive immune system to recognize a broad spectrum of pathogens.
• Clonal selection concentrates effector mechanisms to target and clear infections efficiently.
• Memory cells remember specific pathogens from primary immune responses, accelerating future responses.

Timeline of Adaptive Immune Responses

• Primary responses can take up to 14 days to resolve infections.
• This process necessitates dendritic cell interaction, T cell engagement, and B-cell activation.
• Immunoglobulin isotypes are limited during this primary response.
• Secondary encounters elicit a more efficient response.
• Secondary immune responses clear pathogens in 3 to 4 days, much faster than the two weeks it takes during a primary response.
• This speed is due to the rapid action of memory cells.

Memory Cells

• Memory cells, created during a primary immune response, respond rapidly to subsequent exposures.
• These cells produce immunoglobulins that have undergone somatic hypermutation and isotype switching.
• Naïve B cell action is limited during secondary responses, focusing energy on high-affinity immunoglobulin production.
• Memory cells also monitor for antigens in tissues beyond secondary lymphoid tissues.
• Clonal expansion yields both B and T memory cells.
• Long-lived memory cells do not directly combat the pathogen that induced their differentiation.
• Instead, they enable a rapid adaptive immune response upon subsequent exposure to the same pathogen.

Memory T Cells

• Memory T cells differ from naïve T cells in cell-surface molecules, locations, and activating APC types.
• Primary adaptive immune responses produce four memory T cell subpopulations: T memory stem cells (TSCM), central memory T cells (TCM), effector memory T cells (TEM), and resident memory T cells (TRM).
• These subsets are further defined by function, location, and cell-surface marker expression.

T Memory Stem Cells (TSCM)

• The TSCM subset is found in circulation and peripheral tissues.
• TSCM cells share traits with both naïve and memory T cells.
• TSCM cells have high survival, self-renewal, and multipotency for other memory T cells.
• TSCM cells can differentiate into central memory T cells and effector memory T cells.

Central Memory T Cells (TCM)

• The TCM subset resides in circulatory and lymphatic systems.
• TCM cells migrate to and from secondary lymphoid tissues.
• TCM cell activation is similar to naïve T cells.
• TCM cells live longer than naïve and effector memory T cells.
• TCM cells express a larger amount of IL-2, which allows them to activate and differentiate into effector cells post-antigen exposure.

Effector Memory T Cells (TEM)

• The TEM subset is found in secondary lymphoid tissues, the circulatory and lymphatic systems.
• TEM cells can migrate into peripheral tissues.
• TEM cells quickly activate and differentiate into effector T cells in peripheral tissues without migrating through secondary lymphoid tissues.
• This is due to their elevated ability to secrete IFN-γ and TNF-α.

Resident Memory T Cells (TRM)

• The TRM subset remains within a peripheral tissue, not re-entering circulation.
• TRM cells function like TEM cells in peripheral tissues.
• TRM cells protect against recurring infection via quick activation and elevated effector function at potential infection sites.

Cell-Surface Marker Expression Differences

• Naïve and memory T cells are differentiated via the CD45 T-cell signaling molecule.
• CD45 has two isoforms: CD45RA and CD45RO.
• Naïve T cells express the CD45RA isoform.
• Memory T cells express the CD45RO isoform, which signals more efficiently and starts memory T-cell activation.
• Other cell-surface markers to differentiate naïve and memory T cells include chemokine receptor CCR7, L-selectin (CD62L), and CD103.

Memory B Cells

• B cells are activated in secondary lymphoid tissues by CD4 helper T cells, occurring in the T-cell zone, where activated B cells start producing IgM.
• Conjugate pairs of T and B cells become a germinal center.
• Activated B cells in the germinal center undergo isotype switching and somatic hypermutation.
• Activated B cells in germinal centers produce effector plasma cells, secreting high-affinity, isotype-switched immunoglobulins.
• These cells can differentiate into memory B cells, producing the same high-affinity, isotype-switched antibodies as the original B cell upon activation.
• Memory B cells localize in the spleen and migrate into other secondary lymphoid tissues through the circulatory and lymphatic systems.

Suppression of Naïve B Cell Activation

• Memory B cells produce high-affinity immunoglobulins of the correct isotype during a second pathogen encounter.
• IgG produced by a reactivated memory B cell inhibits naïve B-cell activation pathways.
• IgG opsonizes the pathogen.
• The Fc component of the bound IgG interacts with an inhibitory receptor, FcγRIIB1, on the surface of the naïve B cell.

Persistence of Memory Cells

• Naïve lymphocytes rely on survival signals through their T-cell receptor or their membrane immunoglobulins.
• Memory lymphocytes can survive for years without apparent survival signals.
• Secreted cytokines can provide survival signals to memory lymphocyte subsets.
• IL-7 and IL-15, for example, promote CD8+ memory T cell survival without T-cell receptor engagement.

Development and Use of Vaccines

• Edward Jenner's work against smallpox was early vaccine development.
• Variolation involved inoculating individuals with smallpox material, like pustule fluid.
• Vaccination involved inoculating individuals with cowpox material.
• Vaccination was as effective as variolation but less risky; variolation caused smallpox in 1% of individuals.
• COVID-19 vaccines: rapid development and production of multiple vaccines against SARS-CoV-2.
• Pfizer/BioNTech and Moderna mRNA vaccines were rapidly developed.
• The similarity of SARS and COVID-19 and 30 years of mRNA vaccine research allowed companies to develop, test, and produce mRNA COVID-19 vaccines in 11 months.

Vaccines and Autism

• A 1998 Lancet study claimed a link between the MMR vaccine and autism.
• It led to anti-vaccine sentiment online and in the media.
• The article was retracted due to irreproducible findings and a conflict of interest, as two businesses supporting Wakefield’s research stood to gain from his work.

Vaccine Strategy

• Vaccination must induce a primary immune response that activates the needed lymphocytes to combat the actual pathogen.
• The primary immune response promotes memory T and B cell generation, protecting against subsequent pathogen contact.
• Memory T and B cell production is the goal of vaccination.

Inactivated Vaccines

• Most vaccines are composed of killed or inactivated pathogens.
• Heat treatment, irradiation, or formalin treatment is used to destroy their ability to cause disease.
• Inactivated vaccines usually require booster doses, as the first dose doesn't elicit sufficient protection.

Live Attenuated Vaccines

• These vaccines use pathogens that have lost the ability to cause disease, but are not killed.
• The attenuated pathogen survives in the host without causing disease, mimicking an infection.
• Live attenuated vaccines often only require a single dose to induce a robust primary immune response.

Toxoid Vaccines

• Vaccines protect against bacterial toxin products.
• Neutralizing toxins via immunoglobulin production can protect against these bacteria.
• Toxins are inactivated by formalin or heat treatment, creating toxoids, as natural toxins cause disease if injected.

Subunit Vaccines

• Neutralizing antibodies can bind to adhesion molecules of intracellular pathogens.
• Neutralizing immunoglobulins can block intracellular pathogen infection.
• Subunit vaccines protect against pathogen adhesion molecules, preventing entry into target cells.

Conjugate Vaccines

• Conjugate vaccines join a weak antigen to a strong antigen, producing a multivalent vaccine with multiple epitopes.
• Some pathogenic bacteria have a polysaccharide capsule that prevents phagocytosis.
• Adults produce opsonizing antibodies against these antigens through T-cell independent responses.
• Small children and the elderly cannot produce these responses.
• Conjugate vaccines link the polysaccharide coat (weak antigen) with a toxoid (strong antigen).
• This drives activation of T cells responding to the toxoid and B cells responding to the polysaccharide.
• Activated B cells produce opsonizing antibodies to the bacterial pathogen's polysaccharide coat.
• Conjugate vaccines commonly require boosters.

Recombinant Vector Vaccines

• These utilize harmless bacteria or attenuated viruses to express a pathogenic antigen, eliciting an adaptive immune response.
• A gene encoding a pathogenic antigen is isolated and placed into a plasmid or a harmless/attenuated virus.
• The vector is introduced to the host, expressing the gene and leading to an adaptive immune response to the pathogenic antigen.

DNA Vaccines

• DNA vaccines act similarly to recombinant vector vaccines.
• DNA vaccines are placed directly into the host, hoping host cells pick up the DNA and incorporate it into their genomic DNA, and there is no use of virus or bacteria as the carrier.

Messenger RNA Vaccines

• mRNA vaccines employ mRNA encoding an antigen target, delivered into a target cell.
• The target cell takes up the mRNA to translate the antigen, inducing an adaptive immune response.
• The mRNA is purified and its nucleotides modified to limit recognition as a PAMP, limiting innate immune responses.
• Pfizer/BioNTech and Moderna rapidly developed two mRNA vaccines expressing a SARS-CoV-2 surface protein to combat COVID-19.
• Two doses of these confer 90%+ protective efficacy against the disease.

Effective Vaccines

• Naïve T and B cells require a costimulatory signal to prevent anergy and ensure proper activation.
• An effective vaccine promotes clonal selection of protective lymphocytes against a pathogen.
• Also effective vaccines ensure lymphocytes receive a proper costimulatory signal.
• Induction of an inflammatory response is important to activate costimulatory signal B7 expression on dendritic cells.
• This signal activates naïve T cells.
• B-cell costimulation is indirectly affected by the inflammatory response.
• Successful vaccine development enables clonal selection and expansion of protective lymphocytes while also inducing inflammation.

Adjuvants

• Induction of an inflammatory response is necessary for a vaccine to work properly.
• Adjuvants are added to vaccines to strengthen the immune response by inducing inflammation.

Is the Vaccine Safe?

• Key questions in vaccine development include:
• Can the antigen revert to being pathogenic?
• Can the antigen induce toxicity?
• Are the adjuvant components safe in humans?
• Was the vaccine developed in an organism that may induce an allergic response?

Is the Vaccine Effective?

• A vaccine must induce the proper immune response and adequate protection against the pathogen.
• Clinical trials determine a vaccine's effectiveness.

What Is the Best Mode of Delivery?

• Many vaccines are injected intramuscularly.
• Others are more effective via different routes.
• Live attenuated rotavirus vaccine is given orally.
• This activates the adaptive immune response within mucosa-associated lymphoid tissue.
• It also promotes lymphocyte activation at likely pathogen infection sites.

Who Should Receive the Vaccine?

• Vaccines against emerging infectious diseases, including Zika, Ebola, and dengue fever, are in development.
• Those most likely to contact these pathogens are the primary population for vaccination.
• If a pathogen can be used as a bioterrorist weapon, who should receive the vaccine?

What Is the Vaccination Schedule?

• Some vaccines require a single dose, simplifying distribution.
• However, some vaccines require a booster.
• Booster shots are concerning where individuals are less trusting of medicine or must travel far to receive one.

How Must the Vaccine Be Stored?

• How a vaccine must be stored impacts its efficacy.
• The first COVID-19 vaccine approved required ultra-low-temperature freezers.
• Some areas lack the equipment or electricity for safe storage of these vaccines.
• Development must include an effective distribution and storage strategy.

Cost vs. Benefit

• Pharmaceutical companies conduct most vaccine research and development.
• These companies engage in extensive cost/benefit analyses of all potential products.
• Cost/benefit analyses lead to questions about whether a pharmaceutical company should primarily serve the population or its stakeholders when developing a vaccine.