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296 ParT TwO Host Defense Mechanisms and Inflammation

MUCOSAL CTLS Toxoplasma gondii have been shown to be protective. Thus mucosal
CD8 CTLs can also be induced in nonviral situations. Significant
M cells have specific receptors for mucosal virus that allow certain questions remain as to the mechanism by which naïve CD8 T
viruses, such as reoviruses, to enter the cells in both NALTs and cells can be triggered to expand into pCTLs and to the rules for
GALTs. It is likely that enteric viruses, such as rotavirus, and expression of effector CTLs and memory in the actual mucosal
respiratory pathogens, such as influenza virus and respiratory compartment that manifests the infection. pCTLs accumulate
syncytial virus (RSV), also enter the mucosal inductive pathway in immunologically privileged sites, but they do not develop a
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via M cells. After enteric infection or immunization, antigen- cytotoxic function until they encounter infected class I MHC-
stimulated CTLs are disseminated from PPs into mesenteric presenting target cells. It is possible that this mechanism protects
lymph nodes via the lymphatic drainage. Oral immunization the common mucosal immune system network from inadvertent
with live virus can thus induce antigen-specific CTLs in both cytotoxic inflammatory events.
mucosal and systemic lymphoid tissues.
MUCOSAL IMMUNE RESPONSES IN EARLY LIFE
KEY CONCEPTS AND AGING
Mucosal Cytotoxic T Cells (CTLs)
Although most of its structures are present at birth, the mucosal
• After enteric infection or immunization, antigen-stimulated CTLs are immune system requires further postnatal development and
disseminated from Peyer patches into mesenteric lymph nodes via maturation before becoming fully functional (Chapter 38). GALTs,
the lymphatic drainage. NALTs, and tonsils are present in humans at birth. The bacterial
• Oral immunization with live virus can induce antigen-specific CTLs in colonization after birth increases the number of immune cells
both mucosal inductive and effector tissues for mucosal immune and germinal centers in these sites and the number of secondary
responses, as well as in systemic lymphoid tissues for serum immune
responses. lymph nodes (e.g., mesenteric lymph nodes and cervical lymph
nodes; Chapter 2) and generate innate lymphoid follicles (ILFs).
Significant changes that occur after bacterial colonization include
Enteric Viruses and Mucosal CTLs an increase in SIgA levels and in the numbers of IgA secreting
CD8 CTLs (Chapter 17) play a central role in rotavirus and cells, Tregs, and Th17 cells. BALT only develops after birth. It is
reovirus immunity. 50,51 Reovirus-induced CTL precursors (pCTLs) clear that the immature mucosal immune system in early life
in GALTs migrate to the systemic compartment. Reovirus-specific cannot protect against infectious pathogens entering mucosal
CD8 CTLs associated with the αβ T cell population are also surfaces. This gap is filled by maternal antibodies, which are
observed in intraepithelial T lymphocytes. Oral delivery of acquired either before birth through the placenta or after birth
rotavirus increases pCTLs in GALTs and results in their dissemina- via ingestion of milk.
tion throughout the murine lymphoid system within 3 weeks.
Moreover, adoptively transferred CD8 T cells mediate the clearance KEY CONCEPTS
of rotavirus infection in severe combined immunodeficiency mice.
Mucosal Immunosenescence
Respiratory Viruses and Mucosal CTLs
• Early mucosal aging is evident in the gastrointestinal (GI) tract immune
Studies of immune responses after intranasal infection with system.
influenza virus in CD4-coreceptor knock-outs or other mice in • Nasal immunization is an effective route for the induction of mucosal
which this subset had been depleted have shown that CD4 T and systemic immune responses in aging mice.
cells do not affect the induction of pCTLs or significantly alter • Dendritic cell (DC)–targeting mucosal adjuvants are able to elicit protec-
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clearance of infection. Clearance of influenza is unaltered by tive pathogen-specific secretory immunoglobulin A (SIgA) antibody
responses in aged mice.
the use of β 2 microglobulin knock-out mice, which lack CD8 T
cells, or of mice that have been treated with monoclonal anti-CD8.
γδ T cells with several Vδ chain specificities increase in the infected Immune functions are known to deteriorate as a result of
site as clearance occurs, which suggests a regulatory role for γδ aging in several species (Chapter 38). The risk and severity of
T cells in antiviral immunity. 53 infections are higher, and the susceptibility to certain types of
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autoimmune diseases and cancer are greater in older adults,
Mucosal AIDS Models for CTL Responses and responses to vaccination are diminished. Aging-associated
Approximately 80% of new HIV-1 infections result from sexual alterations of the systemic immune compartments have
transmission (Chapter 39). Studies using the rhesus macaque been studied extensively. Dysfunctions occur in both B and T
and the simian immunodeficiency virus (SIV) vaginal infection cells, although the latter are considered more susceptible to
model have provided evidence that pCTLs occur in female immunosenescence.
macaque reproductive tissues and that infection with SIV induces In humans, older subjects were reported to have significantly
CTL responses. This important finding was extended to vaginal higher concentrations of salivary sIgA antibodies compared with
infection with an SIV/HIV-1 chimeric virus (SHIV) containing younger subjects, whereas whole gut lavages of aged and young
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the HIV-1 89.6 env gene. Other work has shown that intranasal subjects contain similar amounts of antibodies. Analogous
immunization with SIV/HIV components induces antibody results have also been obtained for total IgA antibody responses
responses in vaginal secretions. in the serum of aged animals and humans. These results indicate
an absence of aging-associated impairment in total IgA antibody
Other Mucosal CTL Systems levels in external secretions.
Salmonella can elicit CD8 T-cell responses, including CTLs, to The GI tract in older adults is particularly susceptible to
expressed proteins, and CD8 T cells induced to the parasite infectious diseases. Antigen-specific mucosal IgA antibody